Heterocyclic compound

ABSTRACT

The present invention relates to a compound which can be useful for the treatment or prevention of SPT-related diseases including cancer and congenital diseases associated with sphingolipid accumulation (including Niemann-Pick disease).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/565,891, filed Oct. 11, 2017, which is a national phase applicationunder 35 U.S.C. § 371 of PCT International Application No.PCT/JP2016/062418, filed Apr. 19, 2016, which claims priority toJapanese Application No. 2015-086195, filed Apr. 20, 2015, each of whichis hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to a novel compound or a salt thereofwhich can have an inhibitory effect on serine palmitoyltransferase(hereinafter, also referred to as “SPT”). The present invention furtherrelates to a medicament which can be useful for the prevention ortreatment of SPT-related diseases including cancer and congenitaldiseases associated with sphingolipid accumulation includingNiemann-Pick disease, etc., comprising the compound or a salt thereof.

BACKGROUND OF THE INVENTION

SPT is an enzyme that catalyzes the reaction through which L-serine andpalmitoyl coenzyme A are condensed to synthesize3-ketodihydrosphingosine, and is involved in the biosynthesis ofsphingolipids. SPT is constituted by a plurality of subunits. 3 types ofSPT subunits are known: SPT1 (also called SPTLC1), SPT2 (also calledSPTLC2) and SPT3 (also called SPTLC3). A complex consisting of subunitsSPT1 and SPT2 and a complex consisting of subunits SPT1 and SPT3 areknown as SPT as a subunit complex.

The sphingolipids include ceramide, sphingomyelin, ganglioside and thelike. The sphingolipids are constituents of cell membranes and are knownto play an important role in maintenance of homeostasis of the membranesand signal transduction while having various physiological activities.Myriocin, which has an inhibitory effect on SPT, is known to inhibit thegrowth of activated lymphocytes, to inhibit the growth of mouse melanomacell lines, and to exhibit an antitumor effect on mouse melanoma tumormodels (Non Patent Literature 1).

Compounds described in Patent Literatures 1 to 6, etc., have been knownso far as compounds having an antitumor effect.

CITATION LIST Patent Literature

-   Patent Literature 1: International Publication No. WO2010/032856-   Patent Literature 2: International Publication No. WO2009/072643-   Patent Literature 3: International Publication No. WO2008/038841-   Patent Literature 4: International Publication No. WO2013/033270-   Patent Literature 5: International Publication No. WO2012/013716-   Patent Literature 6: International Publication No. WO2001/036403

Non Patent Literature

-   Non Patent Literature 1: Cancer Biology & Therapy 2012, 13: 92-100

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a compound that has anexcellent SPT inhibitory effect and is sufficiently satisfactory as amedicament.

Solution to Problem

The present inventors have conducted diligent studies in light of theobject described above and consequently completed the present inventionby finding that a compound represented by the formula given below canhave the activity of inhibiting SPT. Specifically, the present inventionrelates to at least the following aspects:

[1] A compound represented by a formula:

wherein

ring Ar represents an optionally further substituted aromaticheterocycle or an optionally further substituted C₆₋₁₄ aromatichydrocarbon ring;

ring A represents an optionally further substituted C₆₋₁₄ aromatichydrocarbon ring or an optionally further substituted heterocycle;

R¹ represents an optionally substituted C₆₋₁₄ aryl group, an optionallysubstituted C₃₋₁₀ cycloalkyl group or an optionally substitutedheterocyclic group except that when R¹ is an optionally substitutedheterocyclic group, R¹ is represented by a formula:

wherein ring B represents an optionally further substituted heterocycle,and[Formula 3]

represents a single bond or a double bond, or a formula:

wherein ring D represents an optionally further substitutednitrogen-containing heterocycle,R² represents a hydrogen atom, orR¹ and R² are bonded to each other to form an optionally substituted 5-or 6-membered aromatic heterocycle or an optionally substituted benzeneringor a salt thereof (in the present specification, the compound or a saltthereof is also referred to as “compound (I)”).

[2] The compound or a salt thereof according to [1], wherein

ring Ar is

(I) an aromatic heterocycle optionally substituted by 1 to 3substituents selected from

(1) a halogen atom,

(2) a cyano group,

(3) a hydroxy group,

(4) an optionally halogenated C₁₋₆ alkyl group,

(5) a C₃₋₁₀ cycloalkyl group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a hydroxy-C₁₋₆ alkoxy group,

(8) a C₃₋₁₀ cycloalkyloxy group,

(9) a C₁₋₆ alkyl-carbonyl group,

(10) a C₁₋₆ alkoxy-carbonyl group,

(11) an amino group,

(12) a mono- or di-C₁₋₆ alkylamino group,

(13) a mono- or di-C₁₋₆ alkyl-carbonylamino group,

(14) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group,

(15) a 5- to 14-membered aromatic heterocyclic group, and

(16) a C₁₋₆ alkylsulfonyl group,

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring optionally substituted by 1 to 3substituents selected from

(1) a halogen atom,

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group,

(4) a C₃₋₁₀ cycloalkyl group,

(5) an optionally halogenated C₁₋₆ alkoxy group,

(6) a mono- or di-C₁₋₆ alkylamino group,

(7) a C₁₋₆ alkyl-5- to 14-membered aromatic heterocyclic group, and

(8) a C₁₋₆ alkylsulfonyl group;

ring A is

(I) a C₆₋₁₄ aromatic hydrocarbon ring optionally substituted by 1 to 3substituents selected from

(1) a halogen atom,

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group,

(4) an optionally halogenated C₁₋₆ alkoxy group, and

(5) a C₁₋₆ alkylsulfonyl group,

or

(II) a heterocycle optionally substituted by 1 to 3 substituentsselected from

(1) a halogen atom,

(2) an optionally halogenated C₁₋₆ alkyl group,

(3) a C₃₋₁₀ cycloalkyl group,

(4) an optionally halogenated C₁₋₆ alkoxy group,

(5) a hydroxy-C₁₋₆ alkoxy group,

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group,

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group,

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group,

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group,

(10) a mono- or di-C₇₋₁₆ aralkyl phosphate-C₁₋₆ alkoxy group,

(11) a 5- to 14-membered aromatic heterocyclic group,

(12) a 5- to 14-membered aromatic heterocyclyloxy group,

(13) a C₁₋₆ alkylsulfonyl group, and

(14) a C₁₋₆ alkylsulfanyl group;

R¹ is

(I) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from

(1) a halogen atom,

(2) an optionally halogenated C₁₋₆ alkyl group, and

(3) a C₁₋₆ alkoxy group,

(II) a C₃₋₁₀ cycloalkyl group, or

(III) an optionally substituted heterocyclic group represented by any of

(1) a heterocyclic group represented by a formula:

which is selected from pyrazolyl, thienyl and pyridyl and optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups, and

(2) a nitrogen-containing heterocyclic group represented by a formula:

which is selected from pyrazol-1-yl, 1,2,3-triazol-1-yl and piperidinyl;

R² is a hydrogen atom; or

R¹ and R² are bonded to each other to form

(I) a 5- or 6-membered aromatic heterocycle optionally substituted by 1to 3 substituents selected from

(1) a halogen atom,

(2) an optionally halogenated C₁₋₆ alkyl group,

(3) a C₇₋₂₀ alkyl group,

(4) a hydroxy-C₁₋₆ alkyl group,

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group,

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group,

(7) a C₃₋₁₀ cycloalkyl group,

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group,

(9) a 3- to 14-membered non-aromatic heterocyclic group,

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group,

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup,

(12) a carbamoyl-C₁₋₆ alkyl group,

(13) an amino-C₁₋₆ alkyl group,

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group,

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group, and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group,

or

(II) a benzene ring optionally substituted by one halogen atom.

[3] The compound or a salt thereof according to [1] or [2], wherein

R¹ represents a C₆₋₁₄ aryl group optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group and (3) a C₁₋₆ alkoxy group,

R² is a hydrogen atom, or

R¹ and R² are bonded to each other to form a 5- or 6-membered aromaticheterocycle optionally substituted by 1 to 3 substituents selected from(1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl group, (3)a C₇₋₂₀ alkyl group, (4) a hydroxy-C₁₋₆ alkyl group, (5) a C₁₋₆alkoxy-C₁₋₆ alkyl group, (6) an optionally halogenated C₃₋₁₀cycloalkyl-C₁₋₆ alkyl group, (7) a C₃₋₁₀ cycloalkyl group, (8) a C₁₋₆alkoxy-C₇₋₁₆ aralkyl group, (9) a 3- to 14-membered non-aromaticheterocyclic group, (10) an optionally halogenated C₁₋₆ alkyl-3- to14-membered non-aromatic heterocyclic group, (11) a C₁₋₆ alkyl-3- to14-membered non-aromatic heterocycle-C₁₋₆ alkyl group, (12) acarbamoyl-C₁₋₆ alkyl group, (13) an amino-C₁₋₆ alkyl group, (14) a C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, (15) a fluorenyl-C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, and (16) a mono- or di-C₁₋₆ alkylnitrogen-containing heterocycle-C₁₋₆ alkyl-nitrogen-containingheterocycle-κ²N (boron halide)-C₁₋₆ alkyl-carbonylamino-C₁₋₆ alkylgroup.

[4] The compound or a salt thereof according to [1] or [3], wherein

ring Ar represents an aromatic heterocycle optionally substituted by 1to 3 substituents selected from (1) a halogen atom, (2) a cyano group,(3) a hydroxy group, (4) an optionally halogenated C₁₋₆ alkyl group, (5)a C₃₋₁₀ cycloalkyl group, (6) an optionally halogenated C₁₋₆ alkoxygroup, (7) a hydroxy-C₁₋₆ alkoxy group, (8) a C₃₋₁₀ cycloalkyloxy group,(9) a C₁₋₆ alkyl-carbonyl group, (10) a C₁₋₆ alkoxy-carbonyl group, (11)an amino group, (12) a mono- or di-C₁₋₆ alkylamino group, (13) a mono-or di-C₁₋₆ alkyl-carbonylamino group, (14) a mono- or di-C₃₋₁₀cycloalkyl-carbonylamino group, (15) a 5- to 14-membered aromaticheterocyclic group, and (16) a C₁₋₆ alkylsulfonyl group.

[5] The compound or a salt thereof according to any of [1] to [4],wherein

(I) ring A represents a heterocycle optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group, (3) a C₃₋₁₀ cycloalkyl group, (4) anoptionally halogenated C₁₋₆ alkoxy group, (5) a hydroxy-C₁₋₆ alkoxygroup, (6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group, (7) a 3- to 14-memberednon-aromatic heterocycle-C₁₋₆ alkoxy group, (8) a 3- to 14-memberednon-aromatic heterocyclyloxy-C₁₋₆ alkoxy group, (9) a mono- or di-C₁₋₆alkylamino-C₁₋₆ alkoxy group, (10) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group, (11) a 5- to 14-membered aromaticheterocyclic group, (12) a 5- to 14-membered aromatic heterocyclyloxygroup, (13) a C₁₋₆ alkylsulfonyl group, and (14) a C₁₋₆ alkylsulfanylgroup,

R¹ represents a C₆₋₁₄ aryl group optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group and (3) a C₁₋₆ alkoxy group, and

R² represents a hydrogen atom, or

(II) ring A represents a C₆₋₁₄ aromatic hydrocarbon ring optionallysubstituted by 1 to 3 substituents selected from (1) a halogen atom, (2)a cyano group, (3) an optionally halogenated C₁₋₆ alkyl group, (4) anoptionally halogenated C₁₋₆ alkoxy group, and (5) a C₁₋₆ alkylsulfonylgroup, and

R¹ and R² are bonded to each other to form a 5- or 6-membered aromaticheterocycle optionally substituted by 1 to 3 substituents selected from(1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl group, (3)a C₇₋₂₀ alkyl group, (4) a hydroxy-C₁₋₆ alkyl group, (5) a C₁₋₆alkoxy-C₁₋₆ alkyl group, (6) an optionally halogenated C₃₋₁₀cycloalkyl-C₁₋₆ alkyl group, (7) a C₃₋₁₀ cycloalkyl group, (8) a C₁₋₆alkoxy-C₇₋₁₆ aralkyl group, (9) a 3- to 14-membered non-aromaticheterocyclic group, (10) an optionally halogenated C₁₋₆ alkyl-3- to14-membered non-aromatic heterocyclic group, (11) a C₁₋₆ alkyl-3- to14-membered non-aromatic heterocycle-C₁₋₆ alkyl group, (12) acarbamoyl-C₁₋₆ alkyl group, (13) an amino-C₁₋₆ alkyl group, (14) a C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, (15) a fluorenyl-C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, and (16) a mono- or di-C₁₋₆ alkylnitrogen-containing heterocycle-C₁₋₆ alkyl-nitrogen-containingheterocycle-κ2N (boron halide)-C₁₋₆ alkyl-carbonylamino-C₁₋₆ alkylgroup.

[6]N-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideor a salt thereof.

[7]N-((7S)-4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamideor a salt thereof.

[8] A medicament comprising a compound or a salt thereof according toany of [1] to [7].

[9] The medicament according to [8], wherein the medicament is a SPTinhibitor.

[10] The medicament according to [8] or [9], wherein the medicament is aprophylactic or therapeutic agent for cancer.

[11] The medicament according to [8] or [9], wherein the medicament is aprophylactic or therapeutic agent for Niemann-Pick disease.

[12] A method for inhibiting SPT in a mammal, comprising administeringan effective amount of a compound or a salt thereof according to any of[1] to [7] to the mammal.

[13] A method for preventing or treating cancer in a mammal, comprisingadministering an effective amount of a compound or a salt thereofaccording to any of [1] to [7] to the mammal.

[14] A method for preventing or treating Niemann-Pick disease in amammal, comprising administering an effective amount of a compound or asalt thereof according to any of [1] to [7] to the mammal.

[15] The compound or a salt thereof according to any of [1] to [7] foruse in the prevention or treatment of cancer.

[16] The compound or a salt thereof according to any of [1] to [7] foruse in the prevention or treatment of Niemann-Pick disease.

[17] Use of a compound or a salt thereof according to any of [1] to [7]for the production of a prophylactic or therapeutic agent for cancer.

[18] Use of a compound or a salt thereof according to any of [1] to [7]for the production of a prophylactic or therapeutic agent forNiemann-Pick disease.

Advantageous Effects of Invention

The compound or the medicament of the present invention can have anexcellent inhibitory effect on SPT. Thus, the compound or the medicamentof the present invention can be used as a SPT inhibitor and can beuseful as a prophylactic or therapeutic agent for diseases that areprobably influenced by SPT, for example, cancer.

DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the compound of the present invention, a method forproducing the same and use of the same will be described in detail.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,

(2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),

(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),

(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),

(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),

(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C₁₋₆ alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group,

(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) a C₆₋₁₄ aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁₋₆ alkoxy-carbonyl group,

(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) a C₆₋₁₄ arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),

(44) an amino group,

(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),

(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),

(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),

(49) a formylamino group,

(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),

(51) a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),

(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),

(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),

(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),

(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C₁₋₆ alkyl group,

(58) a C₂₋₆ alkenyl group,

(59) a C₂₋₆ alkynyl group,

(60) a C₃₋₁₀ cycloalkyl group,

(61) a C₃₋₁₀ cycloalkenyl group and

(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl)aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl)(C₆₋₁₄ aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₁₋₆ alkylene group”include —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH(CH₃)—, —C(CH₃)₂—, —CH(C₂H₅)—, —CH(C₃H₇)—, —CH(CH(CH₃)₂)—,—(CH(CH₃))₂—, —CH₂—CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂—CH₂—C(CH₃)₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—C(CH₃)₂— and —C(CH₃)₂—CH₂—CH₂—CH₂—.

In the present specification, examples of the “C₂₋₆ alkenylene group”include —CH═CH—, —CH₂—CH═CH—, —CH═CH—CH₂—, —C(CH₃)₂—CH═CH—,—CH═CH—C(CH₃)₂—, —CH₂—CH═CH—CH₂—, —CH₂—CH₂—CH═CH—, —CH═CH—CH₂—CH₂—,—CH═CH—CH═CH—, —CH═CH—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH═CH—.

In the present specification, examples of the “C₂₋₆ alkynylene group”include —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —C(CH₃)₂—C≡C—, —C≡C—C(CH₃)₂—,—CH₂—C≡C—CH₂—, —CH₂—CH₂—C≡C—, —C≡C—CH₂—CH₂—, —C≡C—C≡C—,—C≡C—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—C≡C—.

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocycle” include anaromatic heterocycle and a non-aromatic heterocycle, each containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom.

In the present specification, examples of the “aromatic heterocycle”include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “aromatic heterocycle” include5- or 6-membered monocyclic aromatic heterocycles such as thiophene,furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole,1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole,tetrazole, triazine and the like; and

8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocycles such as benzothiophene, benzofuran, benzimidazole,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole,benzotriazole, imidazopyridine, thienopyridine, furopyridine,pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine,imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine,pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine,thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine,naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole,purine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and thelike.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and

9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include a “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, examples of the “C₇₋₂₀ alkyl group”include heptyl, octyl, decyl, octadecyl, nonadecyl and icosyl.

Hereinafter, the definition of each symbol in the formula (I) will bedescribed in detail.

The “aromatic heterocycle” in the “optionally further substitutedaromatic heterocycle” represented by ring Ar is preferably quinoxaline,pyridine, thiophene, furan, pyrrole, pyrazole, thiazole, isoxazole,pyridine, pyrimidine, pyridazine, benzothiophene, benzofuran,benzimidazole, benzoxazole, benzothiazole, benzotriazole,pyrrolopyridine, pyrazolopyridine, imidazopyrimidine, imidazopyridine,imidazopyridazine, thienopyridine, 1H-indazole, 2H-indazole, quinoline,quinazoline or triazolopyridine.

The “aromatic heterocycle” in the “optionally further substitutedaromatic heterocycle” represented by ring Ar is more preferablyquinoxaline, thiophene, pyrrole, pyrazole, thiazole, isoxazole,pyridine, pyridazine, benzothiophene, benzofuran, benzimidazole,benzoxazole, benzothiazole, benzotriazole, pyrrolopyridine,pyrazolopyridine, imidazopyrimidine, imidazopyridine, imidazopyridazine,thienopyridine, 1H-indazole, 2H-indazole, quinoline, quinazoline ortriazolopyridine.

The “aromatic heterocycle” in the “optionally further substitutedaromatic heterocycle” represented by ring Ar is further preferablyquinoxaline or imidazopyridine.

In an alternative embodiment, the “aromatic heterocycle” in the“optionally further substituted aromatic heterocycle” represented byring Ar is preferably pyridine, furan, pyrazole, thiazole, isoxazole,pyrimidine, pyridazine, benzothiophene, benzimidazole, benzothiazole,imidazopyridine or quinoxaline, more preferably pyridine.

The “C₆₋₁₄ aromatic hydrocarbon ring” in the “optionally furthersubstituted C₆₋₁₄ aromatic hydrocarbon ring” represented by ring Ar ispreferably benzene or naphthalene, more preferably benzene.

Ring Ar is preferably

(I) an aromatic heterocycle (particularly, quinoxaline, pyridine,thiophene, furan, pyrrole, pyrazole, thiazole, isoxazole, pyridine,pyrimidine, pyridazine, benzothiophene, benzofuran, benzimidazole,benzoxazole, benzothiazole, benzotriazole, pyrrolopyridine,pyrazolopyridine, imidazopyrimidine, imidazopyridine, imidazopyridazine,thienopyridine, 1H-indazole, 2H-indazole, quinoline, quinazoline,triazolopyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) a hydroxy group,

(4) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, trifluoromethyl),

(5) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(6) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,(²H₃) methoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, isopropoxy),

(7) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(8) a C₃₋₁₀ cycloalkyloxy group (particularly, cyclohexyloxy),

(9) a C₁₋₆ alkyl-carbonyl group (particularly, acetyl),

(10) a C₁₋₆ alkoxy-carbonyl group (particularly, methoxycarbonyl,ethoxycarbonyl),

(11) an amino group,

(12) a mono- or di-C₁₋₆ alkylamino group (particularly, methylamino,dimethylamino),

(13) a mono- or di-C₁₋₆ alkyl-carbonylamino group (particularly,acetylamino),

(14) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group (particularly,cyclopropylcarbonylamino, di(cyclopropylcarbonyl)amino),

(15) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl), and

(16) a C₁₋₆ alkylsulfonyl group (particularly, isopropylsulfonyl),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1)substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, trifluoromethyl),

(4) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(5) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,trifluoromethoxy, ethoxy, isopropoxy),

(6) a mono- or di-C₁₋₆ alkylamino group (particularly, dimethylamino),

(7) a C₁₋₆ alkyl-5- to 14-membered aromatic heterocyclic group(particularly, methyl-1,2,4-oxadiazolyl), and

(8) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl).

Ring Ar is more preferably

(I) an aromatic heterocycle (particularly, quinoxaline, thiophene,pyrrole, pyrazole, thiazole, isoxazole, pyridine, pyridazine,benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole,benzotriazole, pyrrolopyridine, pyrazolopyridine, imidazopyrimidine,imidazopyridine, imidazopyridazine, thienopyridine, 1H-indazole,2H-indazole, quinoline, quinazoline, triazolopyridine) optionallysubstituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) a hydroxy group,

(4) a C₁₋₆ alkyl group (particularly, methyl),

(5) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(6) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,(²H₃) methoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(7) a C₁₋₆ alkyl-carbonyl group (particularly, acetyl),

(8) a C₁₋₆ alkoxy-carbonyl group (particularly, methoxycarbonyl,ethoxycarbonyl),

(9) an amino group,

(10) a mono- or di-C₁₋₆ alkylamino group (particularly, dimethylamino),

(11) a mono- or di-C₁₋₆ alkyl-carbonylamino group (particularly,acetylamino),

(12) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group (particularly,cyclopropylcarbonylamino, di(cyclopropylcarbonyl)amino),

(13) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl), and

(14) a C₁₋₆ alkylsulfonyl group (particularly, isopropylsulfonyl),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1)substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl),

(4) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(5) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,trifluoromethoxy, ethoxy), and

(6) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl).

Ring Ar is further preferably an 8- to 14-membered fused bicyclicaromatic heterocycle (particularly, quinoxaline, imidazopyridine)optionally substituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) a C₁₋₆ alkyl group (particularly, methyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy).

The “C₆₋₁₄ aromatic hydrocarbon ring” in the “optionally furthersubstituted C₆₋₁₄ aromatic hydrocarbon ring” represented by ring A ispreferably benzene or naphthalene, particularly preferably benzene.

The “heterocycle” in the “optionally further substituted heterocycle”represented by ring A is preferably thiophene, furan, pyrazole,thiazole, pyridine, oxazole, isoxazole, imidazole, pyrazine, benzofuran,1,3-benzodioxole, 2,3-dihydrobenzofuran, dihydrooxazole ordihydropyridine.

The “heterocycle” in the “optionally further substituted heterocycle”represented by ring A is more preferably pyrazole, pyridine, oxazole,isoxazole, thiazole, imidazole or pyrazine, further preferably pyridineor pyrazole.

In an alternative embodiment, the “heterocycle” in the “optionallyfurther substituted heterocycle” represented by ring A is morepreferably thiophene, furan, pyrazole, thiazole, pyridine, benzofuran,1,3-benzodioxole or 2,3-dihydrobenzofuran.

Ring A is preferably

(I) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

or

(II) a heterocycle (particularly, thiophene, furan, pyrazole, thiazole,pyridine, oxazole, isoxazole, imidazole, pyrazine, benzofuran,1,3-benzodioxole, 2,3-dihydrobenzofuran, dihydrooxazole,dihydropyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an oxo group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(4) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(5) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(6) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(7) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(8) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(9) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(10) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(11) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(12) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(13) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(14) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(15) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl).

Ring A is more preferably

(I) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene) optionallysubstituted by 1 to 3 (particularly, 1) substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

(II) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyrazole, pyridine, oxazole, isoxazole, thiazole, imidazole, pyrazine)optionally substituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(3) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(5) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(10) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(11) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(12) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(13) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(14) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl),

or

(III) a 3- to 8-membered monocyclic non-aromatic heterocycle(particularly, dihydrooxazole, dihydropyridine) optionally substitutedby 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a C₁₋₆ alkyl group (particularly, methyl), and

(2) an oxo group.

Ring A is further preferably a 5- or 6-membered monocyclic aromaticheterocycle (particularly, pyridine or pyrazole) optionally substitutedby 1 to 3 substituents selected from a halogen atom (particularly, achlorine atom), an optionally halogenated C₁₋₆ alkyl group(particularly, methyl, trifluoromethyl), and an optionally halogenatedC₁₋₆ alkoxy group (particularly, difluoromethoxy, ethoxy).

R¹ is preferably

(I) a C₆₋₁₄ aryl group (particularly, phenyl) optionally substituted by1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy),

(II) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl, cyclopentyl,cyclohexyl), or

(III) an optionally substituted heterocyclic group represented by any of

(1) a heterocyclic group represented by a formula:

which is selected from pyrazolyl (particularly, pyrazol-3-yl,pyrazol-4-yl), thienyl (particularly, thiophen-2-yl) and pyridyl(particularly, pyridin-3-yl, pyridin-4-yl) and optionally substituted by1 to 3 C₁₋₆ alkyl groups (particularly, methyl),and

(2) a nitrogen-containing heterocyclic group represented by a formula:

which is selected from pyrazol-1-yl, 1,2,3-triazol-1-yl and piperidinyl.

R¹ is more preferably phenyl optionally substituted by 1 to 3(particularly, 1) halogen atoms (particularly, a fluorine atom).

R² is preferably a hydrogen atom.

In an alternative embodiment, ring Ar is more preferably

(I) an aromatic heterocycle (particularly, pyridine, furan, pyrazole,thiazole, isoxazole, pyrimidine, pyridazine, benzothiophene,benzimidazole, benzothiazole, imidazopyridine, quinoxaline) optionallysubstituted by 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, isopropoxy),

(3) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(4) a C₃₋₁₀ cycloalkyloxy group (particularly, cyclohexyloxy),

(5) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(6) a mono- or di-C₁₋₆ alkylamino group (particularly, methylamino,dimethylamino),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,trifluoromethoxy, ethoxy, isopropoxy),

(5) a mono- or di-C₁₋₆ alkylamino group (particularly, dimethylamino),

(6) a C₁₋₆ alkyl-5- to 14-membered aromatic heterocyclic group(particularly, methyl-1,2,4-oxadiazolyl), and

(7) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl).

In an alternative embodiment, ring Ar is further preferably

(I) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyridine) optionally substituted by 1 to 3 (particularly, 2)substituents selected from

(1) a halogen atom (particularly, a chlorine atom), and

(2) a C₁₋₆ alkoxy group (particularly, methoxy),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 2) substituents selectedfrom a C₁₋₆ alkoxy group (particularly, methoxy).

In an alternative embodiment, ring A is more preferably

(I) a C₆₋₁₄ aromatic hydrocarbon ring (preferably benzene, naphthalene)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

or

(II) a heterocycle (particularly, thiophene, furan, pyrazole, thiazole,pyridine, benzofuran, 1,3-benzodioxole, 2,3-dihydrobenzofuran)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a chlorine atom), and

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl).

In an alternative embodiment, ring A is further preferably a C₆₋₁₄aromatic hydrocarbon ring (particularly, benzene) optionally substitutedby 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl), and

(3) an optionally halogenated C₁₋₆ alkoxy group (particularly,trifluoromethoxy).

In an alternative embodiment, R¹ and R² are more preferably bonded toeach other to form

(I) a 5- or 6-membered aromatic heterocycle (particularly, pyrazole,imidazole, isothiazole, isoxazole, pyridine) optionally substituted by 1to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,butyl, isobutyl, 2,2-dimethylpropyl),

(3) a C₇₋₂₀ alkyl group (particularly, octadecyl),

(4) a hydroxy-C₁₋₆ alkyl group (particularly, 3-hydroxy-3-methylbutyl),

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (particularly, 2-methoxyethyl),

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group(particularly, cyclopropylmethyl, 1-fluorocyclopropylmethyl),

(7) a C₃₋₁₀ cycloalkyl group (particularly, cyclobutyl, cyclopentyl),

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group (particularly, methoxybenzyl),

(9) a 3- to 14-membered non-aromatic heterocyclic group (particularly,tetrahydropyranyl),

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group (particularly, 2,2,2-trifluoroethylazetidinyl),

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup (particularly, methyloxetanylmethyl),

(12) a carbamoyl-C₁₋₆ alkyl group (particularly, carbamoylmethyl),

(13) an amino-C₁₋₆ alkyl group (particularly, aminopentyl),

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group (particularly,tert-butoxycarbonylaminopentyl),

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group(particularly, fluorenylmethoxycarbonylaminopentyl), and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group (particularly,dimethylpyrrolyl-κN-methylene-pyrrolyl-κN(difluoroboron)-propanoylaminopentyl),

or

(II) a benzene ring optionally substituted by one halogen atom(particularly, a chlorine atom).

In an alternative embodiment, R¹ and R² are further preferably bonded toeach other to form a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyrazole) optionally substituted by 1 to 3(particularly, 1) substituents selected from

(1) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, isopropyl).

Preferable specific examples of the compound (I) include the following:Compound (AB):

Compound (I) wherein

ring Ar is

(I) an aromatic heterocycle (particularly, quinoxaline, pyridine,thiophene, furan, pyrrole, pyrazole, thiazole, isoxazole, pyridine,pyrimidine, pyridazine, benzothiophene, benzofuran, benzimidazole,benzoxazole, benzothiazole, benzotriazole, pyrrolopyridine,pyrazolopyridine, imidazopyrimidine, imidazopyridine, imidazopyridazine,thienopyridine, 1H-indazole, 2H-indazole, quinoline, quinazoline,triazolopyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) a hydroxy group,

(4) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(5) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(6) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,(²H₃) methoxy, difluoromethoxy, ethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, isopropoxy),

(7) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(8) a C₃₋₁₀ cycloalkyloxy group (particularly, cyclohexyloxy),

(9) a C₁₋₆ alkyl-carbonyl group (particularly, acetyl),

(10) a C₁₋₆ alkoxy-carbonyl group (particularly, methoxycarbonyl,ethoxycarbonyl),

(11) an amino group,

(12) a mono- or di-C₁₋₆ alkylamino group (particularly, methylamino,dimethylamino),

(13) a mono- or di-C₁₋₆ alkyl-carbonylamino group (particularly,acetylamino),

(14) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group (particularly,cyclopropylcarbonylamino, di(cyclopropylcarbonyl)amino),

(15) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl), and

(16) a C₁₋₆ alkylsulfonyl group (particularly, isopropylsulfonyl),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1)substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, trifluoromethyl),

(4) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(5) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,trifluoromethoxy, ethoxy, isopropoxy),

(6) a mono- or di-C₁₋₆ alkylamino group (particularly, dimethylamino),

(7) a C₁₋₆ alkyl-5- to 14-membered aromatic heterocyclic group(particularly, methyl-1,2,4-oxadiazolyl), and

(8) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl);

ring A is

(I) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

or

(II) a heterocycle (particularly, thiophene, furan, pyrazole, thiazole,pyridine, oxazole, isoxazole, imidazole, pyrazine, benzofuran,1,3-benzodioxole, 2,3-dihydrobenzofuran, dihydrooxazole,dihydropyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(3) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(5) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(10) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(11) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(12) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(13) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(14) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl);

R¹ is

(I) a C₆₋₁₄ aryl group (particularly, phenyl) optionally substituted by1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy),

(II) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl, cyclopentyl,cyclohexyl), or

(III) an optionally substituted heterocyclic group represented by any of

(1) a heterocyclic group represented by a formula:

which is selected from pyrazolyl (particularly, pyrazol-3-yl,pyrazol-4-yl), thienyl (particularly, thiophen-2-yl) and pyridyl(particularly, pyridin-3-yl, pyridin-4-yl) and optionally substituted by1 to 3 C₁₋₆ alkyl groups (particularly, methyl), and

(2) a nitrogen-containing heterocyclic group represented by a formula:

which is selected from pyrazol-1-yl, 1,2,3-triazol-1-yl and piperidinyl;

R² is a hydrogen atom; or

R¹ and R² are bonded to each other to form

(I) a 5- or 6-membered aromatic heterocycle (particularly, pyrazole,imidazole, isothiazole, isoxazole, pyridine) optionally substituted by 1to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,butyl, isobutyl, 2,2-dimethylpropyl),

(3) a C₇₋₂₀ alkyl group (particularly, octadecyl),

(4) a hydroxy-C₁₋₆ alkyl group (particularly, 3-hydroxy-3-methylbutyl),

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (particularly, 2-methoxyethyl),

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group(particularly, cyclopropylmethyl, 1-fluorocyclopropylmethyl),

(7) a C₃₋₁₀ cycloalkyl group (particularly, cyclobutyl, cyclopentyl),

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group (particularly, methoxybenzyl),

(9) a 3- to 14-membered non-aromatic heterocyclic group (particularly,tetrahydropyranyl),

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group (particularly, 2,2,2-trifluoroethylazetidinyl),

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup (particularly, methyloxetanylmethyl),

(12) a carbamoyl-C₁₋₆ alkyl group (particularly, carbamoylmethyl),

(13) an amino-C₁₋₆ alkyl group (particularly, aminopentyl),

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group (particularly,tert-butoxycarbonylaminopentyl),

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group(particularly, fluorenylmethoxycarbonylaminopentyl), and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group (particularly,dimethylpyrrolyl-κN-methylene-pyrrolyl-κN(difluoroboron)-propanoylaminopentyl),

or

(II) a benzene ring optionally substituted by one halogen atom(particularly, a chlorine atom).

Compound (B-1):

Compound (AB) wherein

ring Ar is

(I) an aromatic heterocycle (particularly, quinoxaline, thiophene,pyrrole, pyrazole, thiazole, isoxazole, pyridine, pyridazine,benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole,benzotriazole, pyrrolopyridine, pyrazolopyridine, imidazopyrimidine,imidazopyridine, imidazopyridazine, thienopyridine, 1H-indazole,2H-indazole, quinoline, quinazoline, triazolopyridine) optionallysubstituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) a hydroxy group,

(4) a C₁₋₆ alkyl group (particularly, methyl),

(5) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(6) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,(²H₃) methoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(7) a C₁₋₆ alkyl-carbonyl group (particularly, acetyl),

(8) a C₁₋₆ alkoxy-carbonyl group (particularly, methoxycarbonyl,ethoxycarbonyl),

(9) an amino group,

(10) a mono- or di-C₁₋₆ alkylamino group (particularly, dimethylamino),

(11) a mono- or di-C₁₋₆ alkyl-carbonylamino group (particularly,acetylamino),

(12) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group (particularly,cyclopropylcarbonylamino, di(cyclopropylcarbonyl)amino),

(13) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl), and

(14) a C₁₋₆ alkylsulfonyl group (particularly, isopropylsulfonyl),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1)substituents selected from

-   -   (1) a halogen atom (particularly, a chlorine atom, a fluorine        atom, a bromine atom),    -   (2) a cyano group,    -   (3) an optionally halogenated C₁₋₆ alkyl group (particularly,        methyl, difluoromethyl),    -   (4) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),    -   (5) an optionally halogenated C₁₋₆ alkoxy group (particularly,        methoxy, trifluoromethoxy, ethoxy), and    -   (6) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl);        ring A is        (I) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)        optionally substituted by 1 to 3 (particularly, 1) substituents        selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

(II) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyrazole, pyridine, oxazole, isoxazole, thiazole, imidazole, pyrazine)optionally substituted by 1 to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(3) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(5) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(10) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(11) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(12) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(13) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(14) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl),

or

(III) a 3- to 8-membered monocyclic non-aromatic heterocycle(particularly, dihydrooxazole, dihydropyridine) optionally substitutedby 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a C₁₋₆ alkyl group (particularly, methyl), and

(2) an oxo group;

R¹ is

(I) a C₆₋₁₄ aryl group (particularly, phenyl) optionally substituted by1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy),

(II) C₃₋₁₀ cycloalkyl (particularly, cyclopropyl, cyclopentyl,cyclohexyl), or

(III) an optionally substituted heterocyclic group represented by any of

(1) a heterocyclic group represented by a formula:

which is selected from pyrazolyl (particularly, pyrazol-3-yl,pyrazol-4-yl), thienyl (particularly, thiophen-2-yl) and pyridyl(particularly, pyridin-3-yl, pyridin-4-yl) and optionally substituted by1 to 3 C₁₋₆ alkyl groups (particularly, methyl), and

(2) a nitrogen-containing heterocyclic group represented by a formula:

which is selected from pyrazol-1-yl, 1,2,3-triazol-1-yl and piperidinyl;and

R² is a hydrogen atom.

Compound (B-2):

Compound (B-1) wherein

ring Ar is an 8- to 14-membered fused bicyclic aromatic heterocycle(particularly, quinoxaline, imidazopyridine) optionally substituted by 1to 3 substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) a C₁₋₆ alkyl group (particularly, methyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy);

ring A is a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyridine or pyrazole) optionally substituted by 1 to 3substituents selected from a halogen atom (particularly, a chlorineatom), an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and an optionally halogenated C₁₋₆ alkoxy group(particularly, difluoromethoxy, ethoxy); and

R¹ is phenyl optionally substituted by 1 to 3 (particularly, 1) halogenatoms (particularly, a fluorine atom).

Compound (A-1):

Compound (AB) wherein

ring Ar is

(I) an aromatic heterocycle (particularly, pyridine, furan, pyrazole,thiazole, isoxazole, pyrimidine, pyridazine, benzothiophene,benzimidazole, benzothiazole, imidazopyridine, quinoxaline) optionallysubstituted by 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, isopropoxy),

(3) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(4) a C₃₋₁₀ cycloalkyloxy group (particularly, cyclohexyloxy),

(5) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(6) a mono- or di-C₁₋₆ alkylamino group (particularly, methylamino,dimethylamino),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (particularly, a fluorine atom, a chlorine        atom),    -   (2) a cyano group,    -   (3) an optionally halogenated C₁₋₆ alkyl group (particularly,        trifluoromethyl),    -   (4) an optionally halogenated C₁₋₆ alkoxy group (particularly,        methoxy, trifluoromethoxy, ethoxy, isopropoxy),    -   (5) a mono- or di-C₁₋₆ alkylamino group (particularly,        dimethylamino),    -   (6) a C₁₋₆ alkyl-5- to 14-membered aromatic heterocyclic group        (particularly, methyl-1,2,4-oxadiazolyl), and    -   (7) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl);        ring A is        (I) a C₆₋₁₄ aromatic hydrocarbon ring (preferably benzene,        naphthalene) optionally substituted by 1 to 3 (particularly, 1        or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl),

or

(II) a heterocycle (particularly, thiophene, furan, pyrazole, thiazole,pyridine, benzofuran, 1,3-benzodioxole, 2,3-dihydrobenzofuran)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a chlorine atom), and

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl); and

R¹ and R² are bonded to each other to form

(I) a 5- or 6-membered aromatic heterocycle (particularly, pyrazole,imidazole, isothiazole, isoxazole, pyridine) optionally substituted by 1to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,butyl, isobutyl, 2,2-dimethylpropyl),

(3) a C₇₋₂₀ alkyl group (particularly, octadecyl),

(4) a hydroxy-C₁₋₆ alkyl group (particularly, 3-hydroxy-3-methylbutyl),

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (particularly, 2-methoxyethyl),

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group(particularly, cyclopropylmethyl, 1-fluorocyclopropylmethyl),

(7) a C₃₋₁₀ cycloalkyl group (particularly, cyclobutyl, cyclopentyl),

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group (particularly, methoxybenzyl),

(9) a 3- to 14-membered non-aromatic heterocyclic group (particularly,tetrahydropyranyl),

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group (particularly, 2,2,2-trifluoroethylazetidinyl),

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup (particularly, methyloxetanylmethyl),

(12) a carbamoyl-C₁₋₆ alkyl group (particularly, carbamoylmethyl),

(13) an amino-C₁₋₆ alkyl group (particularly, aminopentyl),

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group (particularly,tert-butoxycarbonylaminopentyl),

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group(particularly, fluorenylmethoxycarbonylaminopentyl), and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group (particularly,dimethylpyrrolyl-κN-methylene-pyrrolyl-κN(difluoroboron)-propanoylaminopentyl),

or

(II) a benzene ring optionally substituted by one halogen atom(particularly, a chlorine atom).

Compound (A-2):

Compound (A-1) wherein

ring Ar is

(I) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyridine) optionally substituted by 1 to 3 (particularly, 2)substituents selected from

(1) a halogen atom (particularly, a chlorine atom), and

(2) a C₁₋₆ alkoxy group (particularly, methoxy),

or

(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 2) substituents selectedfrom a C₁₋₆ alkoxy group (particularly, methoxy);

ring A is a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl), and

(3) an optionally halogenated C₁₋₆ alkoxy group (particularly,trifluoromethoxy); and

R¹ and R² are bonded to each other to form a 5- or 6-membered monocyclicaromatic heterocycle (particularly, pyrazole) optionally substituted by1 to 3 (particularly, 1) substituents selected from an optionallyhalogenated C₁₋₆ alkyl group (particularly, methyl, ethyl,2,2-difluoroethyl, isopropyl).

Compound (AB-1):

Compound (AB) wherein

ring Ar is an aromatic heterocycle (particularly, quinoxaline, pyridine,thiophene, furan, pyrrole, pyrazole, thiazole, isoxazole, pyridine,pyrimidine, pyridazine, benzothiophene, benzofuran, benzimidazole,benzoxazole, benzothiazole, benzotriazole, pyrrolopyridine,pyrazolopyridine, imidazopyrimidine, imidazopyridine, imidazopyridazine,thienopyridine, 1H-indazole, 2H-indazole, quinoline, quinazoline,triazolopyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom, abromine atom),

(2) a cyano group,

(3) a hydroxy group,

(4) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(5) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(6) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,(²H₃) methoxy, difluoromethoxy, ethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, isopropoxy),

(7) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(8) a C₃₋₁₀ cycloalkyloxy group (particularly, cyclohexyloxy),

(9) a C₁₋₆ alkyl-carbonyl group (particularly, acetyl),

(10) a C₁₋₆ alkoxy-carbonyl group (particularly, methoxycarbonyl,ethoxycarbonyl),

(11) an amino group,

(12) a mono- or di-C₁₋₆ alkylamino group (particularly, methylamino,dimethylamino),

(13) a mono- or di-C₁₋₆ alkyl-carbonylamino group (particularly,acetylamino),

(14) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group (particularly,cyclopropylcarbonylamino, di(cyclopropylcarbonyl)amino),

(15) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl), and

(16) a C₁₋₆ alkylsulfonyl group (particularly, isopropylsulfonyl),

(I) ring A is a heterocycle (particularly, thiophene, furan, pyrazole,thiazole, pyridine, oxazole, isoxazole, imidazole, pyrazine, benzofuran,1,3-benzodioxole, 2,3-dihydrobenzofuran, dihydrooxazole,dihydropyridine) optionally substituted by 1 to 3 substituents selectedfrom

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(3) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(5) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(10) a mono- or di-C₇₋₁₆ aralkylphosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(11) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(12) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(13) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(14) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl),

R¹ is a C₆₋₁₄ aryl group (particularly, phenyl) optionally substitutedby 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl) and

(3) a C₁₋₆ alkoxy group (particularly, methoxy), and

R² is a hydrogen atom, or

(II) ring A is a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

R¹ and R² are bonded to each other to form a 5- or 6-membered aromaticheterocycle (particularly, pyrazole, imidazole, isothiazole, isoxazole,pyridine) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,butyl, isobutyl, 2,2-dimethylpropyl),

(3) a C₇₋₂₀ alkyl group (particularly, octadecyl),

(4) a hydroxy-C₁₋₆ alkyl group (particularly, 3-hydroxy-3-methylbutyl),

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (particularly, 2-methoxyethyl),

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group(particularly, cyclopropylmethyl, 1-fluorocyclopropylmethyl),

(7) a C₃₋₁₀ cycloalkyl group (particularly, cyclobutyl, cyclopentyl),

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group (particularly, methoxybenzyl),

(9) a 3- to 14-membered non-aromatic heterocyclic group (particularly,tetrahydropyranyl),

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group (particularly, 2,2,2-trifluoroethylazetidinyl),

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup (particularly, methyloxetanylmethyl),

(12) a carbamoyl-C₁₋₆ alkyl group (particularly, carbamoylmethyl),

(13) an amino-C₁₋₆ alkyl group (particularly, aminopentyl),

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group (particularly,tert-butoxycarbonylaminopentyl),

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group(particularly, fluorenylmethoxycarbonylaminopentyl), and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ2N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group (particularly,dimethylpyrrolyl-κN-methylene-pyrrolyl-κN(difluoroboron)-propanoylaminopentyl).

Compound (AB-2):

Compound (AB-1) wherein

(I) ring A is a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyrazole, pyridine, oxazole, isoxazole, thiazole,imidazole, pyrazine) optionally substituted by 1 to 3 substituentsselected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,difluoromethyl, 2,2-difluoroethyl, trifluoromethyl, isopropyl,tert-butyl),

(3) a C₃₋₁₀ cycloalkyl group (particularly, cyclopropyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy),

(5) a hydroxy-C₁₋₆ alkoxy group (particularly, 2-hydroxyethoxy),

(6) a C₁₋₆ alkoxy-C₁₋₆ alkoxy group (particularly, 2-methoxyethoxy),

(7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxy group(particularly, morpholinylethoxy, morpholinylpropoxy),

(8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxy group(e.g., tetrahydropyranyloxyethoxy),

(9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group (particularly,dimethylamino-ethoxy, dimethylamino-propoxy),

(10) a mono- or di-C₇₋₁₆ aralkyl phosphate-C₁₋₆ alkoxy group(particularly, dibenzylphosphateethoxy),

(11) a 5- to 14-membered aromatic heterocyclic group (particularly,pyrazolyl),

(12) a 5- to 14-membered aromatic heterocyclyloxy group (particularly,triazolopyridinyloxy),

(13) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl), and

(14) a C₁₋₆ alkylsulfanyl group (particularly, methylsulfanyl); and

R¹ is a C₆₋₁₄ aryl group (particularly, phenyl) optionally substitutedby 1 to 3 (particularly, 1 or 2) substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and

(3) a C₁₋₆ alkoxy group (particularly, methoxy), or

(II) ring A is a C₆₋₁₄ aromatic hydrocarbon ring (preferably benzene,naphthalene) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl),

(4) an optionally halogenated C₁₋₆ alkoxy group (particularly, methoxy,difluoromethoxy, trifluoromethoxy), and

(5) a C₁₋₆ alkylsulfonyl group (particularly, methylsulfonyl); and

R¹ and R² are bonded to each other to form a 5- or 6-membered aromaticheterocycle (particularly, pyrazole, imidazole, isothiazole, isoxazole,pyridine) optionally substituted by 1 to 3 (particularly, 1 or 2)substituents selected from

(1) a halogen atom (particularly, a chlorine atom, a bromine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, isopropyl,butyl, isobutyl, 2,2-dimethylpropyl),

(3) a C₇₋₂₀ alkyl group (particularly, octadecyl),

(4) a hydroxy-C₁₋₆ alkyl group (particularly, 3-hydroxy-3-methylbutyl),

(5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group (particularly, 2-methoxyethyl),

(6) an optionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group(particularly, cyclopropylmethyl, 1-fluorocyclopropylmethyl),

(7) a C₃₋₁₀ cycloalkyl group (particularly, cyclobutyl, cyclopentyl),

(8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group (particularly, methoxybenzyl),

(9) a 3- to 14-membered non-aromatic heterocyclic group (particularly,tetrahydropyranyl),

(10) an optionally halogenated C₁₋₆ alkyl-3- to 14-membered non-aromaticheterocyclic group (particularly, 2,2,2-trifluoroethylazetidinyl),

(11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkylgroup (particularly, methyloxetanylmethyl),

(12) a carbamoyl-C₁₋₆ alkyl group (particularly, carbamoylmethyl),

(13) an amino-C₁₋₆ alkyl group (particularly, aminopentyl),

(14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group (particularly,tert-butoxycarbonylaminopentyl),

(15) a fluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group(particularly, fluorenylmethoxycarbonylaminopentyl), and

(16) a mono- or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group (particularly,dimethylpyrrolyl-κN-methylene-pyrrolyl-κN(difluoroboron)-propanoylaminopentyl).

Compound (AB-3):

Compound (AB-2) wherein

(I) ring A is a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyridine, pyrazole) optionally substituted by 1 to 3substituents selected from a halogen atom (particularly, a chlorineatom), an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and an optionally halogenated C₁₋₆ alkoxy group(particularly, difluoromethoxy, ethoxy); and

R¹ is phenyl optionally substituted by 1 to 3 (particularly, 1) halogenatoms (particularly, a fluorine atom), or

(II) ring A is a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl), and

(3) an optionally halogenated C₁₋₆ alkoxy group (particularly,trifluoromethoxy); and

R¹ and R² are bonded to each other to form a 5- or 6-membered monocyclicaromatic heterocycle (particularly, pyrazole) optionally substituted by1 to 3 (particularly, 1) substituents selected from

(1) an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,ethyl, 2,2-difluoroethyl, isopropyl).

Compound (B-3):

Compound (I) wherein

ring Ar is an 8- to 14-membered fused bicyclic aromatic heterocycle(particularly, quinoxaline) optionally substituted by 1 to 3substituents selected from a halogen atom (particularly, a chlorineatom) and a C₁₋₆ alkyl group (particularly, methyl);

ring A is a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyridine or pyrazole) optionally substituted by 1 to 3substituents selected from a halogen atom (particularly, a chlorineatom), an optionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and an optionally halogenated C₁₋₆ alkoxy group(particularly, difluoromethoxy, ethoxy);

R¹ is a C₆₋₁₄ aryl group (particularly, phenyl) optionally substitutedby 1 to 3 (particularly, 1) halogen atom (particularly, a fluorineatom); and

R² is a hydrogen atom.

Compound (A-3):

Compound (I) wherein

ring Ar is a 5- or 6-membered monocyclic aromatic heterocycle(particularly, pyridine) optionally substituted by 1 to 3 (particularly,2) substituents selected from (1) a halogen atom (particularly, achlorine atom), and (2) a C₁₋₆ alkoxy group (particularly, methoxy);

ring A is a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from

(1) a halogen atom (particularly, a chlorine atom),

(2) an optionally halogenated C₁₋₆ alkyl group (particularly,trifluoromethyl), and

(3) an optionally halogenated C₁₋₆ alkoxy group (particularly,trifluoromethoxy); and

R¹ and R² are bonded to each other to form a 5- or 6-membered monocyclicaromatic heterocycle (particularly, pyrazole) optionally substituted by1 to 3 (particularly, 1) substituents selected from an optionallyhalogenated C₁₋₆ alkyl group (particularly, methyl, ethyl,2,2-difluoroethyl, isopropyl).

Compound (AB-4):

Compound (I) wherein

ring Ar is

(I) an 8- to 14-membered fused bicyclic aromatic heterocycle(particularly, quinoxaline) optionally substituted by 1 to 3substituents selected from a halogen atom (particularly, a chlorineatom) and a C₁₋₆ alkyl group (particularly, methyl), or

(II) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyridine) optionally substituted by 1 to 3 (particularly, 2)substituents selected from (1) a halogen atom (particularly, a chlorineatom), and (2) a C₁₋₆ alkoxy group (particularly, methoxy);

ring A is

(I) a 5- or 6-membered monocyclic aromatic heterocycle (particularly,pyridine or pyrazole) optionally substituted by 1 to 3 substituentsselected from (1) a halogen atom (particularly, a chlorine atom), (2) anoptionally halogenated C₁₋₆ alkyl group (particularly, methyl,trifluoromethyl), and (3) an optionally halogenated C₁₋₆ alkoxy group(particularly, difluoromethoxy, ethoxy), or(II) a C₆₋₁₄ aromatic hydrocarbon ring (particularly, benzene)optionally substituted by 1 to 3 (particularly, 1 or 2) substituentsselected from (1) a halogen atom (particularly, a chlorine atom), (2) anoptionally halogenated C₁₋₆ alkyl group (particularly, trifluoromethyl),and (3) an optionally halogenated C₁₋₆ alkoxy group (particularly,trifluoromethoxy);

R¹ is a C₆₋₁₄ aryl group (particularly, phenyl) optionally substitutedby 1 to 3 (particularly, 1) halogen atom (particularly, a fluorineatom);

R² is a hydrogen atom; or

R¹ and R² are bonded to each other to form a 5- or 6-membered monocyclicaromatic heterocycle (particularly, pyrazole) optionally substituted by1 to 3 (particularly, 1) substituents selected from an optionallyhalogenated C₁₋₆ alkyl group (particularly, methyl, ethyl,2,2-difluoroethyl, isopropyl).

The salt of the compound (I) is preferably a pharmacologicallyacceptable salt. Examples thereof include a salt with an inorganic base,a salt with an organic base, a salt with an inorganic acid, a salt withan organic acid and a salt with a basic or acidic amino acid.

Preferable examples of the salt with an inorganic base include: analkali metal salt such as sodium salt, potassium salt and the like; analkaline earth metal salt such as calcium salt, magnesium salt and thelike; and an aluminum salt and an ammonium salt.

Preferable examples of the salt with an organic base include a salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine,benzylamine, dicyclohexylamine or N,N-dibenzylethylenediamine.

Preferable examples of the salt with an inorganic acid include a saltwith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid.

Preferable examples of the salt with an organic acid include a salt withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid.

Preferable examples of the salt with a basic amino acid include a saltwith arginine, lysine or omithine.

Preferable examples of the salt with an acidic amino acid include a saltwith aspartic acid or glutamic acid.

The method for producing the compound of the present invention will bedescribed below.

A starting material or a reagent used in each step in the productionmethod given below and the obtained compound may each form a salt.Examples of such a salt include the same as the aforementioned salt ofthe compound of the present invention, and the like.

When the compound obtained in each step is a free compound, thiscompound can be converted to a salt of interest by a method known per sein the art. On the contrary, when the compound obtained in each step isa salt, this salt can be converted to a free form or another type ofsalt of interest by a method known per se in the art.

The compound obtained in each step may be used in the next reaction inthe form of its reaction solution or after being obtained as a crudeproduct. Alternatively, the compound obtained in each step can beisolated and/or purified from the reaction mixture by a separationapproach such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography or thelike according to a routine method.

If a starting material or a reagent compound for each step iscommercially available, the commercially available product can be useddirectly.

In the reaction of each step, the reaction time may differ depending onthe reagent or the solvent used and is usually 1 minute to 48 hours,preferably 10 minutes to 8 hours, unless otherwise specified.

In the reaction of each step, the reaction temperature may differdepending on the reagent or the solvent used and is usually −78° C. to300° C., preferably −78° C. to 150° C., unless otherwise specified.

In the reaction of each step, the pressure may differ depending on thereagent or the solvent used and is usually 1 atm to 20 atm, preferably 1atm to 3 atm, unless otherwise specified.

In the reaction of each step, a microwave synthesis apparatus, forexample, Initiator manufactured by Biotage Japan Ltd., may be used. Thereaction temperature may differ depending on the reagent or the solventused and is usually room temperature to 300° C., preferably 50° C. to250° C., unless otherwise specified. The reaction time may differdepending on the reagent or the solvent used and is usually 1 minute to48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

In the reaction of each step, the reagent is used at 0.5 equivalents to20 equivalents, preferably 0.8 equivalents to 5 equivalents, withrespect to the substrate, unless otherwise specified. In the case ofusing the reagent as a catalyst, the reagent is used at 0.001equivalents to 1 equivalent, preferably 0.01 equivalents to 0.2equivalents, with respect to the substrate. When the reagent also servesas a reaction solvent, the reagent is used in the amount of the solvent.

In the reaction of each step, this reaction is carried out without asolvent or by dissolution or suspension in an appropriate solvent,unless otherwise specified. Specific examples of the solvent include asolvent described in Examples and the following:

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol andthe like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran,1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, hexane and the like;

amides: N,N-dimethylformamide, N-methylpyrrolidone and the like;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

acid anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and thelike;

inorganic acids: hydrochloric acid, sulfuric acid and the like;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like; and

water.

Two or more of these solvents may be used as a mixture at an appropriateratio.

In the case of using a base in the reaction of each step, for example,the following base or a base described in Examples is used:

inorganic bases: sodium hydroxide, magnesium hydroxide and the like;

basic salts: sodium carbonate, calcium carbonate, sodium bicarbonate andthe like;

organic bases: triethylamine, diethylamine, pyridine,4-dimethylaminopyridine, N,N-dimethylaniline,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,imidazole, piperidine and the like;

metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide and the like; and

organic lithiums: n-butyllithium and the like.

In the case of using an acid or an acidic catalyst in the reaction ofeach step, for example, the following acid or acidic catalyst or an acidor an acidic catalyst described in Examples is used:

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid,hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; and

Lewis acids: boron trifluoride-diethyl ether complex, zinc iodide,anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ironchloride and the like.

The reaction of each step is carried out according to a method known perse in the art, for example, a method described in The Fifth Series ofExperimental Chemistry, Vol. 13 to Vol. 19 (edited by The ChemicalSociety of Japan); Shin Jikken Kagaku Koza (New Experimental Chemistryin English), Vol. 14 to Vol. 15 (edited by The Chemical Society ofJapan); Syntheses in the Organic Chemistry Laboratory, Revised, 2nd Ed.(L. F. Tietze, Th. Eicher, Nankodo Co., Ltd.); Organic Name Reactions;The Reaction Mechanism and Essence, Revised (Hideo Tougo, KodanshaLtd.); Organic Syntheses Collective Volume I to VII (John Wiley & Sons,Inc.); Modern Organic Synthesis in the Laboratory: A Collection ofStandard Experimental Procedures (Jie Jack Li, Oxford University Press);Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (ElsevierJapan KK); Strategic Applications of Named Reactions in OrganicSynthesis (translated by Kiyoshi Tomioka, published by Kagaku-DojinPublishing Company, Inc.); Comprehensive Organic Transformations (VCHPublishers, Inc.) (1989), etc., or a method described in Examples,unless otherwise specified.

In each step, the protection or deprotection reaction of a functionalgroup is carried out according to a method known per se in the art, forexample, a method described in “Protective Groups in Organic Synthesis,4th Ed.” (Theodora W. Greene, Peter G. M. Wuts), Wiley-Interscience(2007); “Protecting Groups, 3rd Ed.” (P. J. Kocienski) Thieme MedicalPublishers (2004), etc., or a method described in Examples.

Examples of a protective group for a hydroxy group in an alcohol or aphenolic hydroxy group or the like include: an ether-type protectivegroup such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilylether, tetrahydropyranyl ether and the like; a carboxylic acidester-type protective group such as acetic acid ester and the like; asulfonic acid ester-type protective group such as methanesulfonic acidester and the like; a carbonic acid ester-type protective group such astert-butyl carbonate and the like; and the like.

Examples of a protective group for a carbonyl group in an aldehydeinclude: an acetal-type protective group such as dimethylacetal and thelike; a cyclic acetal-type protective group such as 1,3-dioxane and thelike; and the like.

Examples of a protective group for a carbonyl group in a ketone include:a ketal-type protective group such as dimethylketal and the like; acyclic ketal-type protective group such as 1,3-dioxane and the like; anoxime-type protective group such as O-methyloxime and the like; ahydrazone-type protective group such as N,N-dimethylhydrazone and thelike; and the like.

Examples of a protective group for a carboxyl group include: anester-type protective group such as methyl ester and the like; anamide-type protective group such as N,N-dimethylamide and the like; andthe like

Examples of a protective group for a thiol include: an ether-typeprotective group such as benzyl thioether and the like; an ester-typeprotective group such as thioacetic acid ester, thiocarbonate,thiocarbamate and the like; and the like.

Examples of a protective group for an amino group or an aromaticheterocycle such as imidazole, pyrrole, indole or the like include: acarbamate-type protective group such as benzyl carbamate and the like;an amide-type protective group such as acetamide and the like; analkylamine-type protective group such as N-triphenylmethylamine and thelike; a sulfonamide-type protective group such as methanesulfonamide andthe like; and the like.

These protective groups can be removed by use of a method known per sein the art, for example, a method using an acid, a base, ultravioletlight, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide) or a reductionmethod.

In the case of carrying out reduction reaction in each step, examples ofthe reducing agent used include: metal hydrides such as lithium aluminumhydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutyl aluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asa borane-tetrahydrofuran complex and the like; Raney nickel; Raneycobalt; hydrogen; formic acid; triethylsilane and the like. In the caseof reducing a carbon-carbon double bond or triple bond, a method using acatalyst such as palladium-carbon, a Lindlar's catalyst or the like canbe used.

In the case of carrying out oxidation reaction in each step, examples ofthe oxidizing agent used include: peracids such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodates such as sodium periodate and the like;a high-valent iodine reagent such as iodosylbenzene and the like; areagent having manganese, such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;a reagent having chromium, such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagents and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;a sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); and the like.

In the case of carrying out radical cyclization reaction in each step,examples of the radical initiator used include: an azo compound such asazobisisobutyronitrile (AIBN) and the like; a water-soluble radicalinitiator such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and the like;triethylboron in the presence of air or oxygen; benzoyl peroxide; andthe like. Examples of the radical reaction agent used includetributylstannane, tris(trimethylsilyl)silane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

In the case of carrying out Wittig reaction in each step, examples ofthe Wittig reagent used include alkylidenephosphoranes and the like. Thealkylidenephosphoranes can be prepared by a method known per se in theart, for example, the reaction between a phosphonium salt and a strongbase.

In the case of carrying out Homer-Emmons reaction in each step, examplesof the reagent used include: phosphonoacetic acid esters such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;and a base such as alkali metal hydrides, organic lithiums and the like.

In the case of carrying out Friedel-Crafts reaction in each step,examples of the reagent used include a combination of a Lewis acid andan acid chloride and a combination of a Lewis acid and an alkylatingagent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, anorganic acid or an inorganic acid may be used instead of the Lewis acid,and an acid anhydride such as acetic anhydride or the like may be usedinstead of the acid chloride.

In the case of carrying out aromatic nucleophilic substitution reactionin each step, a nucleophile (e.g., amines, imidazole, etc.) and a base(e.g., basic salts, organic bases, etc.) are used as reagents.

In the case of carrying out nucleophilic addition reaction using acarbanion, nucleophilic 1,4-addition reaction (Michael additionreaction) using a carbanion or nucleophilic substitution reaction usinga carbanion in each step, examples of the base used for generating thecarbanion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

In the case of carrying out Grignard reaction in each step, examples ofthe Grignard reagent include: aryl magnesium halides such as phenylmagnesium bromide and the like; and alkyl magnesium halides such asmethyl magnesium bromide and the like. The Grignard reagent can beprepared by a method known per se in the art, for example, the reactionbetween alkyl halide or aryl halide and metal magnesium with ether ortetrahydrofuran as a solvent.

In the case of carrying out Knoevenagel condensation reaction in eachstep, an active methylene compound flanked by two electron-attractinggroups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asreagents.

In the case of carrying out Vilsmeier-Haack reaction in each step,phosphoryl chloride and an amide derivative (e.g.,N,N-dimethylformamide, etc.) are used as reagents.

In the case of carrying out azidation reaction of alcohols, alkylhalides or sulfonic acid esters in each step, examples of the azidatingagent used include diphenylphosphorylazide (DPPA), trimethylsilylazide,sodium azide and the like. In the case of azidating, for example,alcohols, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, or the like can be used.

In the case of carrying out reductive amination reaction in each step,examples of the reducing agent used include sodiumtriacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acidand the like. When the substrate is an amine compound, examples of thecarbonyl compound used include p-formaldehyde as well as aldehydes suchas acetaldehyde and the like, and ketones such as cyclohexanone and thelike. When the substrate is a carbonyl compound, examples of the aminesused include: ammonia; primary amine such as methylamine and the like;secondary amine such as dimethylamine and the like; and the like.

In the case of carrying out Mitsunobu reaction in each step,azodicarboxylic acid esters (e.g., diethyl azodicarboxylate (DEAD),diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine areused as reagents.

In the case of carrying out esterification reaction, amidation reactionor ureation reaction in each step, examples of the reagent used include:an acyl halide form of acid chloride, acid bromide and the like; andactivated carboxylic acids such as an acid anhydride, an active esterform, a sulfuric acid ester form and the like. Examples of the activatorfor carboxylic acid include: a carbodiimide condensing agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; a triazine condensing agent such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; a carbonic acid estercondensing agent such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphorylazide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformate such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; and combinations thereof; andthe like. In the case of using a carbodiimide condensing agent, anadditive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide(HOSu), dimethylaminopyridine (DMAP) or the like may be further addedfor the reaction.

In the case of carrying out coupling reaction in each step, examples ofthe metal catalyst used include: a palladium compound such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride,palladium(II) acetate and the like; a nickel compound such astetrakis(triphenylphosphine)nickel(0) and the like; a rhodium compoundsuch as tris(triphenylphosphine)rhodium(III) chloride and the like; acobalt compound; a copper compound such as copper oxide, copper(I)iodide and the like; a platinum compound; and the like. A base may befurther added for the reaction. Examples of such a base includeinorganic bases, basic salts and the like.

In the case of carrying out thiocarbonylation reaction in each step,diphosphorus pentasulfide is typically used as a thiocarbonylatingagent. A reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfidestructure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson's reagent) or the like may be used instead of diphosphoruspentasulfide.

In the case of carrying out Wohl-Ziegler reaction in each step, examplesof the halogenating agent used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. The reaction can be accelerated by the furtheraddition of a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile or the like for the reaction.

In the case of carrying out halogenation reaction of a hydroxy group ineach step, examples of the halogenating agent used include a hydrohalicacid and an acid halide of an inorganic acid, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, and 48% hydrobromic acid and the like for bromination.Also, a method for obtaining an alkyl halide form from an alcohol by theaction of triphenylphosphine and carbon tetrachloride or carbontetrabromide or the like may be used. Alternatively, a method forsynthesizing an alkyl halide form through 2-stage reactions involvingthe conversion of an alcohol to sulfonic acid ester and the subsequentreaction with lithium bromide, lithium chloride or sodium iodide may beused.

In the case of carrying out Arbuzov reaction in each step, examples ofthe reagent used include: alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

In the case of carrying out sulfonic acid esterification reaction ineach step, examples of the sulfonylating agent used includemethanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonicanhydride, p-toluenesulfonic anhydride and the like.

In the case of carrying out hydrolysis reaction in each step, an acid ora base is used as a reagent. In the case of carrying out acid hydrolysisreaction of tert-butyl ester, formic acid, triethylsilane or the likemay be added for reductively trapping a by-product tert-butyl cation.

In the case of carrying out dehydration reaction in each step, examplesof the dehydrating agent used include sulfuric acid, diphosphoruspentoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

In the case of carrying out alkylation reaction of alcohols, amines oran aromatic heterocycle having a NH group in the ring (e.g., imidazole,pyrazole) or the like in each step, examples of the alkylating agentinclude optionally substituted alkyl halide (e.g., iodomethane),optionally substituted alkyl having an optionally substituted C₁₋₆alkylsulfonyloxy group as a leaving group, optionally substituted alkylhaving a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group, sodium 2-chloro-2,2-difluoroacetate,2,2-difluoro-2-(fluorosulfonyl)acetic acid and the like. Examples of thebase used include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

In the case of carrying out coupling reaction in each step, examples ofthe coupling reaction include Suzuki coupling, Stille coupling, Buchwaldcoupling, Negishi coupling, Heck coupling, cyanation reaction usingcopper cyanide or zinc cyanide, and the like. The reagent, such as ametal catalyst, a phosphine ligand, and a base, used in the couplingreaction can be used according to a method known per se in the art[e.g., a method described in J. F. Hartwig, S. Shekhar, Q. Shen, F.Barrios-Landeros, in The Chemistry of Anilines, Z. Rappoport, Ed.,Wiley-Interscience, New York (2007); L. Jiang, S. L. Buchwald, inMetal-Catalyzed Cross-Coupling Reactions, 2nd Ed., A. de Meijere, F.Diederich, Eds., Wiley-VCH, Weinheim, Germany (2004); J. F. Hartwig, inHandbook of Organopalladium Chemistry for Organic Synthesis, A. deMeijere, F. Diederich, Eds., Wiley, New York (2002); J. F. Hartwig, inModern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, (2000)] ora method equivalent thereto, in addition to the reagent mentioned above.

In the case of carrying out Michael reaction in each step, examples ofthe reagent used include acrylic acid esters. Examples of the reactionconditions include conditions under which the reaction is carried out inan acid solvent such as acetic acid, and base (e.g., organic bases,metal alkoxides, inorganic bases) addition conditions.

In the case of carrying out decarboxylation reaction of a carboxylicacid in each step, an acid or a base is used. Hydrolysis of an ester anddecarboxylation of a carboxylic acid may be performed in one step.

In the case of carrying out oximation reaction and imination reaction ofa ketone in each step, hydroxylamine or amine is used as a reagent. Thereaction can be accelerated by the addition of an acid or a base (e.g.,organic bases, inorganic bases) or by the removal of water from thereaction system using a Dean-Stark apparatus.

In the case of carrying out halogenation reaction of an aromatic ring ineach step, examples of the reagent used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like.

In the case of carrying out Curtius reaction in each step, examples ofthe reagent used include diphenylphosphorylazide (DPPA),trimethylsilylazide, sodium azide and the like.

Hereinafter, the method for producing the compound (I) will bedescribed.

Each symbol in the reaction schemes given below represents the samemeaning as above, unless otherwise specified. Each starting compound canbe readily obtained as a commercially available product or can beproduced by a method known per se in the art or a method equivalentthereto, unless a specific method for producing the starting compound ismentioned.

Compound (Ia) included in the compound (I) can be produced by a methodshown in the following reaction scheme 1 or a method equivalent thereto:

In the reaction scheme, ring represents an optionally substituted 5- or6-membered aromatic heterocycle or benzene ring,

P¹ and P² represent different protective groups for an amino group(e.g., a benzyl group and a tert-butoxycarbonyl group) which can bedeprotected under different reaction conditions, and the other symbolsrepresent the same meaning as above.

Examples of the “optionally substituted 5- or 6-membered aromaticheterocycle” represented by ring F include the “optionally substituted5- or 6-membered aromatic heterocycle” formed by R¹ and R² bonded toeach other.

Compound (8a) can be produced by a method shown in the followingreaction scheme 2 or a method equivalent thereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (6a) can be produced from compound (1a) by a method shown inthe following reaction scheme 3 or a method equivalent thereto:

In the reaction scheme, R³ and R⁴ each independently represent a C₁₋₆alkyl group, and the other symbols represent the same meaning as above.

Compound (1a) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (16a) for use in reaction scheme 1 can also be produced by amethod shown in the following reaction scheme 4 or a method equivalentthereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (17a) can also be produced by a method shown in the followingreaction scheme 5 or a method equivalent thereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (21a) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (18a) for use in reaction scheme 4 can also be produced by amethod shown in the following reaction scheme 6 or a method equivalentthereto:

In the reaction scheme, X represents a halogen atom (e.g., a bromineatom, an iodine atom), an optionally halogenated C₁₋₆ alkylsulfonyloxygroup (e.g., methanesulfonyloxy, ethanesulfonyloxy,trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate)), oran optionally substituted C₆₋₁₄ arylsulfonyloxy group (e.g., ap-toluenesulfonyl group), and the other symbols represent the samemeaning as above.

Compound (24a) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (25a) can be produced from compound (24a) through reaction with4-bromo-1-butene in the presence of a base (e.g., organic bases, metalalkoxides, inorganic bases).

Compound (27a) can be produced by subjecting compound (26a) tointramolecular Heck reaction. The reagents and the reaction conditionsmentioned above can be used as a metal catalyst, a phosphine ligand, anda base.

Compound (18a′) included in the compound (18a) can be produced by amethod shown in the following reaction scheme 7 or a method equivalentthereto:

In the reaction scheme, ring F represents a nitrogen-containing5-membered aromatic heterocycle,

R⁵ represents an optionally substituted C₁₋₂₀ alkyl group, and

the other symbols represent the same meaning as above.

Examples of the nitrogen-containing 5-membered aromatic heterocyclerepresented by ring F include a 5-membered ring containing one or morenitrogen atoms as a ring-constituting atom, among the 5- or 6-memberedaromatic heterocycles in the “optionally substituted 5- or 6-memberedaromatic heterocycle” formed by R¹ and R² bonded thereto.

Compound (1a′) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

As mentioned later, other compounds included in the compound (I) orsalts thereof can also be produced by the conversion of a substituent(i.e., the introduction of a substituent or functional group conversion)in the compound (I) by the application of an approach known per se inthe art.

For example, as shown in the following reaction scheme 8, compound(Ia-1) or compound (Ia-2) can be produced by introducing a substituentto compound (Ia).

In the reaction scheme, Y represents a halogen atom (e.g., a bromineatom, an iodine atom),

R⁵ represents a substituent, and

the other symbols represent the same meaning as above.

Compound (Ib) included in the compound (I) can be produced by a methodshown in the following reaction scheme 9 or a method equivalent thereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (3b) can be produced by a method shown in the followingreaction scheme 10 or a method equivalent thereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (1b) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (3b) can be produced by a method shown in the followingreaction scheme 11 or a method equivalent thereto:

In the reaction scheme, R⁶ represents an optionally substituted C₇₋₁₆aralkyl group, and

the other symbols represent the same meaning as above.

Compound (Ib) included in the compound (I) can be produced by a methodshown in the following reaction scheme 12 or a method equivalentthereto:

In the reaction scheme, each symbol represents the same meaning asabove.

As mentioned later, other compounds included in the compound (I) orsalts thereof can also be produced by the conversion of a substituent(i.e., the introduction of a substituent or functional group conversion)in the compound (I) by the application of an approach known per se inthe art.

For example, when compound (Ib) has a leaving group (e.g., a halogenatom, a sulfonyl ester group) in ring A, compound (Ib-1) can be producedby a method shown in the reaction scheme 13 given below or a methodequivalent thereto.

When compound (Ib) has a protected hydroxy group (e.g., a methoxy group,a benzyloxy group) in ring A, compound (Ib-2) can be produced by amethod shown in the following reaction scheme 13 or a method equivalentthereto:

In the reaction scheme, R⁷ represents an optionally substituted C₁₋₆alkoxy group or an optionally substituted C₁₋₆ alkylamino group, and

the other symbols represent the same meaning as above.

Compound (Ib-3) included in the compound (I) can be produced by a methodshown in the following reaction scheme 14 or a method equivalentthereto:

In the reaction scheme, P³ represents a protective group for a hydroxygroup (e.g., a tert-butyldimethylsilyl group), and

the other symbols represent the same meaning as above.

Compound (18b) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (Ib-3) can also be produced by a method shown in the followingreaction scheme 15 or a method equivalent thereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (16b) for use in reaction scheme 12 can be produced by a methodshown in the following reaction scheme 16 or a method equivalentthereto:

In the reaction scheme, each symbol represents the same meaning asabove.

Compound (37b) is commercially available or can be produced by a methodknown per se in the art or a method equivalent thereto.

Compound (38b) can be produced through the reaction of compound (37b)with trifluoromethanesulfonic anhydride in the presence of a base (e.g.,organic bases, metal alkoxides, inorganic bases).

In the conversion of compound (41b) to compound (42b), a base (e.g.,organic bases, metal alkoxides, inorganic bases) can be used forisomerization, if necessary.

Depending on the type of a substituent in a starting compound, thestarting compound differing in substituent therefrom can be produced bythe application of an approach known per se in the art using a compoundproduced by any of the production methods described above as a startingmaterial.

The compound (I), which is a product of these reactions, or a saltthereof may be produced as a single compound or as a mixture.

The compound (I) thus obtained or a salt thereof can be isolated and/orpurified by a separation approach known per se in the art, for example,concentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, dissolution, chromatography or thelike.

The compound (I) obtained in a free form can be converted to a salt ofinterest by a method known per se in the art or a method equivalentthereto. On the other hand, the compound (I) obtained in a salt form canbe converted to a free form or a different salt of interest by a methodknown per se in the art or a method equivalent thereto.

Other compounds included in the compound (I) or salts thereof can alsobe produced by the conversion of a substituent (i.e., the introductionof a substituent or functional group conversion) in the compound (I)thus obtained by the application of an approach known per se in the art.

A general method known in the art is used as a method for theintroduction of a substituent or the functional group conversion.Examples thereof include conversion of a halogen atom (e.g., fluorine,chlorine, bromine, iodine) or an optionally halogenated C₁₋₆alkylsulfonyl-oxy group [e.g., methanesulfonyloxy, ethanesulfonyloxy,trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy (triflate)] toa methyl group, a cyclopropyl group, a vinyl group, a cyano group, aformyl group, a carbonyl group, a carboxyl group, a hydroxy group, anamino group, a boryl group or the like, conversion of a formyl group toan ethynyl group through Seyferth-Gilbert homologation reaction,conversion to a carboxy group by hydrolysis of an ester, conversion of acarboxy group to a carbamoyl group by amidation, conversion of a carboxygroup to a hydroxymethyl group by reduction, conversion of a carbonylgroup to an alcohol form by reduction or alkylation, reductive aminationof a carbonyl group, oximation of a carbonyl group, acylation of anamino group, ureation of an amino group, sulfonylation of an aminogroup, alkylation of an amino group, substitution or amination of activehalogen using amine, alkylation of a hydroxy group and substitution oramination of a hydroxy group.

For this introduction of a substituent or functional group conversion, aprotective group is introduced beforehand to a reactive site, ifpresent, at which unintended reaction occurs, by an approach known perse in the art according to the need, and after the reaction of interest,the protective group can be removed again by an approach known per se inthe art to produce a compound included in the scope of the presentinvention.

When a starting compound or an intermediate has, for example, an aminogroup, a carboxyl group or a hydroxy group as a substituent, the groupmay be protected with a protective group as generally used in peptidechemistry or the like. In this case, after the reaction, the protectivegroup can be removed according to the need to obtain the compound ofinterest.

When the compound (I) has isomers such as optical isomers,stereoisomers, positional isomers, rotational isomers or the like,either of the isomers and a mixture thereof are both included in thecompound (I). When the compound (I) has, for example, optical isomers,the optical isomers resolved from a racemate are also included in thecompound (I). These isomers can each be obtained as a single product bya synthesis approach and a separation approach known per se in the art(e.g., concentration, solvent extraction, column chromatography,recrystallization).

The compound (I) may be crystalline. A single crystal form and a mixtureof crystal forms are both included in the compound (I). The crystals canbe produced by crystallization by the application of a crystallizationmethod known per se in the art.

Also, the compound (I) may be a pharmaceutically acceptable cocrystal orcocrystal salt. In this context, the cocrystal or the cocrystal saltmeans a crystalline substance constituted by two or more unique solidsat room temperature, each having distinctive physical properties (e.g.,structure, melting point, heat of melting, hygroscopicity, stability).The cocrystal and the cocrystal salt can be produced according to acocrystallization method known per se in the art.

The compound (I) may be a hydrate, a non-hydrate, a solvate or anon-solvate. All of them are included in the compound (I).

A compound labeled or substituted with an isotope (e.g., ²H, ³H, ¹¹C,¹⁴C, ¹⁸F, ³⁵S, ¹²⁵I) or the like is also included in the compound (I).The compound (I) labeled or substituted with an isotope can be used as,for example, a tracer (PET tracer), in positron emission tomography(PET) and can be useful in fields of medical diagnosis and the like.

The compound (I) may be a prodrug.

The prodrug of the compound (I) refers to a compound that is convertedto the compound (I) through a reaction caused by an enzyme, gastric acidor the like under physiological conditions in vivo, i.e., a compoundthat is converted to the compound (I) by enzymatic oxidation, reduction,hydrolysis, etc., or a compound that is converted to the compound (I) byhydrolysis, etc., caused by gastric acid or the like.

Examples of the prodrug of the compound (I) include:

(1) a compound in which amino of the compound (I) is acylated, alkylatedor phosphorylated (e.g., a compound in which amino of the compound (I)is eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated,tert-butylated, ethoxycarbonylated, tert-butoxycarbonylated, acetylated,cyclopropylcarbonylated, etc.);(2) a compound in which hydroxy of the compound (I) is acylated,alkylated, phosphorylated or borated (e.g., a compound in which hydroxyof the compound (I) is acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated,dimethylaminomethylcarbonylated, etc.); and(3) a compound in which carboxy of the compound (I) is esterified oramidated (e.g., a compound in which carboxy of the compound (I) isethyl-esterified, phenyl-esterified, carboxymethyl-esterified,dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified,ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-esterified,cyclohexyloxycarbonylethyl-esterified, methylamidated, etc.). Thesecompounds can be produced from the compound (I) by a method known per sein the art.

The prodrug of the compound (I) may be converted to the compound (I)under physiological conditions as described in Iyakuhin No Kaihatsu(Development of Pharmaceuticals in English), Vol. 7, Molecular Design,p. 163-198, Hirokawa Shoten Ltd. (1990).

The compound (I) or the prodrug thereof (in the present specification,these are also collectively referred to as the “compound of the presentinvention”) can have SPT inhibitory activity and can be useful as aprophylactic or therapeutic agent for cancer, a cancer growth inhibitor,a cancer metastasis inhibitor, a prophylactic or therapeutic agent forNiemann-Pick disease, an anti-inflammatory agent, an immunomodulatoryagent, an antianxiety agent and an anticonvulsant agent.

The compound of the present invention can have selective inhibitoryactivity against SPT. In addition, the compound of the present inventioncan be expected to be also excellent in efficacy development,pharmacokinetics (e.g., absorbability, distribution, metabolism,excretion), solubility (e.g., water solubility), interaction with othermedicaments (e.g., drug-metabolizing enzyme inhibitory effect), safety(e.g., acute toxicity, chronic toxicity, genotoxicity, reproductivetoxicity, cardiotoxicity, carcinogenicity, central toxicity) andstability (e.g., chemical stability, stability against enzymes) and cantherefore be useful as a medicament.

The compound of the present invention can have selective inhibitoryactivity against SPT and can therefore be useful as a prophylactic ortherapeutic agent for cancer with reduced toxicity to normal cells.

Thus, the compound of the present invention is capable of inhibitingexcessive (abnormal) SPT effects in a mammal (e.g., a mouse, a rat, ahamster, a rabbit, a cat, a dog, cattle, sheep, a monkey, a human).

The compound of the present invention can be used as a medicament suchas a prophylactic or therapeutic agent for diseases that are probablyinfluenced by SPT (in the present specification, also referred to as“SPT-related diseases”), for example, cancer [e.g., large intestinecancer (e.g., colon cancer, rectal cancer, anus cancer, familialcolorectal cancer, hereditary non-polyposis colorectal cancer,gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lungcancer (lung adenocarcinoma, etc.), small-cell lung cancer, malignantmesothelioma), mesothelioma, pancreatic cancer (e.g., ductal pancreaticcancer, pancreatic endocrine tumor), throat cancer, voice box cancer,head and neck cancer, esophageal cancer, stomach cancer (e.g., papillaryadenocarcinoma, mucous adenocarcinoma, adenosquamous carcinoma),duodenal cancer, small intestine cancer, breast cancer (e.g., invasiveductal breast cancer, noninvasive ductal breast cancer, inflammatorybreast cancer), ovarian cancer (e.g., epithelial ovarian cancer,extragonadal germ cell tumor, ovarian germ cell tumor, ovarian tumor oflow malignant potential), testicular tumor, prostate cancer (e.g.,hormone-dependent prostate cancer, hormone-independent prostate cancer,castration-resistant prostate cancer), liver cancer (e.g.,hepatocellular cancer, primary liver cancer, extrahepatic bile ductcancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer(e.g., renal cell cancer (e.g., clear cell renal cell carcinoma),transitional cell cancer of the renal pelvis and ureter), uterine cancer(e.g., uterine cervical cancer, uterine body cancer, uterine sarcoma),gestational choriocarcinoma, brain tumor (e.g., medulloblastoma, glioma,pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma,anaplastic astrocytoma, pituitary adenoma), retinoblastoma, skin cancer(e.g., basalioma, malignant melanoma), sarcoma (e.g., rhabdomyosarcoma,leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignantbone tumor, bladder cancer, blood cancer (e.g., multiple myeloma,leukemia, malignant lymphoma, Hodgkin disease, chronicmyeloproliferative disease), primary unknown cancer], a cancer growthinhibitor, a cancer metastasis inhibitor, an apoptosis promoter, atherapeutic agent for premalignant lesions (e.g., myelodysplasticsyndrome) or the like.

The compound of the present invention can also be useful as aprophylactic agent or a therapeutic agent for other SPT-related diseases(e.g., heart diseases (cardiomegaly, acute heart failure and chronicheart failure including congestive heart failure, cardiomyopathy, anginapectoris, myocarditis, arrhythmia, tachycardia, myocardial infarction,etc.), myocardial ischemia, venous insufficiency, post-myocardialinfarction heart failure, hypertension, cor pulmonale, arteriosclerosisincluding atherosclerosis (aneurysm, coronary arteriosclerosis, cerebralarteriosclerosis, peripheral arteriosclerosis, etc.), vascularhypertrophy, vascular hypertrophy or occlusion and organ disorder afterintervention (percutaneous transluminal coronary angioplasty, stentplacement, coronary angioscopy, intravascular ultrasonography,intracoronary thrombolytic therapy, etc.), vascular reocclusion orrestenosis after bypass surgery, respiratory diseases (acute pulmonarydisorder), bone diseases (non-metabolic bone diseases such as fracture,refracture, bone deformity or osteoarthritis, osteosarcoma, myeloma,dysostosis, scoliosis and the like; bone defect, osteoporosis,osteomalacia, rachitis, osteitis fibrosa, renal osteodystrophy, Behcet'sdisease in bone, ankylosing spondylitis, chronic rheumatoid arthritis,osteoarthritis knees and destruction of joint tissues in similardiseases thereto, etc.), diabetic complications (retinopathy,nephropathy, neuropathy, macroangiopathy, etc.), chronic rheumatoidarthritis, osteoarthritis, rheumatoid myelitis, neurodegenerativediseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, AIDS encephalopathy, etc.), central nervous system disorders(disorders such as cerebral hemorrhage and cerebral infarction and thelike, and sequelae or complications thereof, spinal cord injury,cerebral edema, encephalomyelitis, etc.), dementia, dysmnesia, impairedconsciousness, amnesia, anxiety symptoms, myotonia symptoms, ischemicperipheral circulatory disturbance, deep vein thrombosis, obstructiveperipheral circulatory disturbance, arteriosclerosis obliterans,thromboangiitis obliterans, diabetic complications (neuropathy,nephropathy, retinopathy, cataract, macroangiopathy, osteopenia,diabetic hyperosmolar coma, infection, diabetic gangrene, oral dryness,decline in hearing, cerebrovascular accident, peripheral arterialdisease, etc.), disturbance of metabolism or malnutrition(hyperlipidemia, hypercholesterolemia, low-HDL cholesterol, impairedglucose tolerance, etc.), insulin resistance syndrome, syndrome X,metabolic syndrome, cerebrovascular accident (asymptomaticcerebrovascular accident, transient ischemic attack, cerebral apoplexy,vascular dementia, hypertensive encephalopathy, cerebral infarction,etc.), cerebral edema, cerebral circulatory disturbance, recurrence andsequelae of cerebrovascular accident (neurological signs, mental signs,subjective symptoms, disturbance in activities of daily living, etc.),renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renalfailure, thrombotic microangiopathy, diabetic nephropathy, nephroticsyndrome, hypertensive nephrosclerosis, complications of dialysis,organopathy including nephritis caused by radiation, etc.), eye diseases(glaucoma, ocular hypertension, etc.), thrombosis, multiple organfailure, endothelial dysfunction, hepatic diseases (hepatitis includinghepatitis C, liver cirrhosis, etc.), gastrointestinal diseases(gastritis, gastric ulcer, stomach cancer, disorders after gastricsurgery, esophageal ulcer, pancreatitis, colorectal polyp,cholelithiasis, inflammatory bowel disease (IBD), etc.), blood orhematopoietic diseases (polycythemia, vascular purpura, disseminatedintravascular coagulation, multiple myeloma, etc.), urological or malegenital diseases (cystitis, benign prostatic hyperplasia, sexuallytransmitted disease, etc.), gynecological diseases (climactericdisorder, gestosis, endometriosis, ovarian disease, mammary glanddisease, sexually transmitted disease, etc.), infectious diseases (viralinfection caused by cytomegalovirus, influenza virus, herpes virus orthe like, rickettsial infection, bacterial infection, etc.), toxemia(sepsis, septic shock, endotoxin shock, gram negative sepsis, toxinshock syndrome, etc.), congenital diseases associated with sphingolipidaccumulation (Fabry disease, Niemann-Pick disease (e.g., types A, B, C,D), Gaucher disease, Tay-Sachs disease)), skin diseases (contactdermatitis, etc.), painful affection (acute and chronic pain, persistentpain (alganesthesia, analgesia, etc.), etc.), inflammation-relateddiseases and immune-related diseases.

Particularly, the compound of the present invention can be useful as aprophylactic or therapeutic agent for cancer or a prophylactic ortherapeutic agent for Niemann-Pick disease.

The compound of the present invention can be orally or parenterallyadministered as a medicament containing the compound of the presentinvention alone or as a mixture with a pharmacologically acceptablecarrier to a mammal (preferably a human).

Hereinafter, the medicament comprising the compound of the presentinvention (also referred to as the “medicament of the presentinvention”) will be described in detail. Examples of the dosage form ofthe medicament of the present invention include an oral preparation suchas tablets (e.g., sugar-coated tablets, film-coated tablets, sublingualtablets, buccal tablets and rapidly orally disintegrating tablets),pills, granules, powders, capsules (e.g., soft capsules andmicrocapsules), syrups, emulsions, suspensions, films (e.g., orallydisintegrating films and patch films for application to the oral mucosa)and the like. Other examples of the dosage form of the medicament of thepresent invention include a parenteral preparation such as injections,transfusions, transdermal preparations (e.g., iontophoresis dermalpreparations), suppositories, ointments, transnasal preparations,transpulmonary preparations, eye drops and the like. Alternatively, themedicament of the present invention may be a controlled-releasepreparation such as a rapid-release preparation, a sustained-releasepreparation (e.g., a sustained-release microcapsule) or the like.

The medicament of the present invention can be produced by a productionmethod known in the art (e.g., a method described in JapanesePharmacopoeia) generally used in the field of pharmaceutical technology.If necessary, the medicament of the present invention can appropriatelycontain an appropriate amount of an additive usually used in thepharmaceutical field, such as an excipient, a binder, a disintegrant, alubricant, a sweetener, a surfactant, a suspending agent, an emulsifier,a colorant, a preservative, a fragrance, a corrigent, a stabilizer, aviscosity modifier and the like.

Examples of the pharmacologically acceptable carrier described aboveinclude these additives.

For example, the tablets can be produced using an excipient, a binder, adisintegrant, a lubricant and the like. The pills and the granules canbe produced using an excipient, a binder and a disintegrant. The powdersand the capsules can be produced using an excipient and the like. Thesyrups can be produced using a sweetener and the like. The emulsions orthe suspensions can be produced using a suspending agent, a surfactant,an emulsifier and the like.

Examples of the excipient include lactose, saccharose, glucose, starch,sucrose, microcrystalline cellulose, licorice powder, mannitol, sodiumbicarbonate, calcium phosphate and calcium sulfate.

Examples of the binder include a solution containing 5 to 10% by weightof starch paste, a solution containing 10 to 20% by weight of gum arabicor gelatin, a solution containing 1 to 5% by weight of tragacanth, acarboxymethylcellulose solution, a sodium alginate solution andglycerin.

Examples of the disintegrant include starch and calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin and simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate,carboxymethylcellulose sodium, methylcellulose and bentonite.

Examples of the emulsifier include gum arabic, tragacanth, gelatin andpolysorbate 80.

When the medicament of the present invention is, for example, tablets,the tablets can be produced according to a method known per se in theart by adding, for example, an excipient (e.g., lactose, saccharose,starch), a disintegrant (e.g., starch, calcium carbonate), a binder(e.g., starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone,hydroxypropylcellulose) or a lubricant (e.g., talc, magnesium stearate,polyethylene glycol 6000) to the compound of the present invention andmolding the mixture by compression, followed by coating, if necessary,by a method known per se in the art for the purpose of taste masking,enteric properties or durability. For example,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxymethylcellulose acetate succinate, Eudragit (manufactured by RohmGmbH, Germany, methacrylic acid-acrylic acid copolymer) and a dye (e.g.,iron red, titanium dioxide) are used as coating agents for the coating.

The injections include intravenous injections as well as subcutaneousinjections, intracutaneous injections, intramuscular injections,intraperitoneal injections, drip injections and the like.

Such injections are prepared by a method known per se in the art, i.e.,by dissolving, suspending or emulsifying the compound of the presentinvention in a sterile aqueous solution or oily solution. Examples ofthe aqueous solution include saline, an isotonic solution containingglucose or an additional adjuvant (e.g., D-sorbitol, D-mannitol, sodiumchloride) and the like. The aqueous solution may contain an appropriatesolubilizing agent, for example, an alcohol (e.g., ethanol), apolyalcohol (e.g., propylene glycol, polyethylene glycol) or a nonionicsurfactant (e.g., polysorbate 80, HCO-50). Examples of the oily solutioninclude sesame oil, soybean oil and the like. The oily solution maycontain an appropriate solubilizing agent. Examples of the solubilizingagent include benzyl benzoate, benzyl alcohol and the like. Theinjections may be further supplemented with a buffer (e.g., a phosphatebuffer solution, a sodium acetate buffer solution), a soothing agent(e.g., benzalkonium chloride, procaine hydrochloride), a stabilizer(e.g., human serum albumin, polyethylene glycol), a preservative (e.g.,benzyl alcohol, phenol) or the like. Ampules are usually filled with theprepared injection solutions.

The content of the compound of the present invention in the medicamentof the present invention differs depending on the form of thepreparation and is usually approximately 0.01 to approximately 100% byweight, preferably approximately 2 to approximately 85% by weight, morepreferably approximately 5 to approximately 70% by weight, with respectto the whole preparation.

The content of the additive in the medicament of the present inventiondiffers depending on the form of the preparation and is usuallyapproximately 1 to approximately 99.9% by weight, preferablyapproximately 10 to approximately 90% by weight, with respect to thewhole preparation.

The compound of the present invention can be used stably, low toxicallyand safely. The daily dose of the compound of the present invention candiffer depending on the status and body weight of a patient, the type ofthe compound, an administration route, etc. In the case of, for example,oral administration to a patient for the purpose of treating cancer, thedaily dose in adult (body weight: approximately 60 kg) can beapproximately 1 to approximately 1000 mg, preferably approximately 3 toapproximately 300 mg, more preferably approximately to approximately 200mg, of the compound of the present invention, which can be administeredin one portion or in two or three portions.

In the case of parenterally administering the compound of the presentinvention, the compound of the present invention is usually administeredin the form of a solution (e.g., an injection). The single dose of thecompound of the present invention also can differ depending on arecipient, a target organ, symptoms, an administration method, etc. Forexample, usually approximately 0.01 to approximately 100 mg, preferablyapproximately 0.01 to approximately 50 mg, more preferably approximately0.01 to approximately 20 mg, of the compound of the present inventionper kg of body weight can be administered by intravenous injection.

The compound of the present invention can be used in combination with anadditional drug. Specifically, the compound of the present invention canbe used in combination with a drug such as a hormone therapeutic, achemotherapeutic, an immunotherapeutic, an agent inhibiting the effectsof a cell growth factor and its receptor, or the like. The compound ofthe present invention can be further used in combination with an enzymereplacement therapeutic, a Chaperone therapeutic, a substrate reductiontherapeutic, a cyclodextrin preparation, gene therapy to express atherapeutic enzyme protein, or cell therapy such as bone marrowtransplantation and the like, for congenital diseases associated withsphingolipid accumulation (including Niemann-Pick disease) or the like.Hereinafter, the drug that may be used in combination with the compoundof the present invention is referred to as a concomitant drug.

Examples of the “hormone therapeutic” that may be used includefosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesteroneacetate, megestrol acetate, chlormadinone acetate, cyproterone acetate,danazol, allylestrenol, gestrinone, mepartricin, raloxifene,ormeloxifene, levormeloxifene, anti-estrogen (e.g., tamoxifen citrate,toremifene citrate), contraceptive pills, mepitiostane, testololactone,aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin,leuprorelin acetate), droloxifene, epitiostanol, ethinyl estradiolsulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride,anastrozole, letrozole, exemestane, vorozole, formestane), anti-androgen(e.g., flutamide, bicalutamide, nilutamide, enzalutamide), 5α-reductaseinhibitors (e.g., finasteride, epristeride, dutasteride), adrenalcorticosteroid agents (e.g., dexamethasone, prednisolone, betamethasone,triamcinolone), androgen synthesis inhibitors (e.g., abiraterone),retinoid and agents delaying retinoid metabolism (e.g., liarozole),thyroid hormones and DDS (drug delivery system) preparations thereof.

Examples of the “chemotherapeutic” that may be used include analkylating agent, an antimetabolite, an anticancer antibiotic and aplant-derived anticancer agent.

Examples of the “alkylating agent” that may be used include nitrogenmustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil,cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosilate, busulfan, nimustine hydrochloride, mitobronitol, melphalan,dacarbazine, ranimustine, estramustine sodium phosphate,triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman,etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin,altretamine, ambamustine, dibrospidium hydrochloride, fotemustine,prednimustine, pumitepa, Ribomustin, temozolomide, treosulfan,trofosfamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesinand DDS preparations thereof.

Examples of the “antimetabolite” that may be used includemercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate,pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabinehydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT,doxifluridine, carmofur, galocitabine, emitefur, capecitabine),aminopterin, nelarabine, leucovorin calcium, Tabloid, butocine, calciumfolinate, calcium levofolinate, cladribine, emitefur, fludarabine,gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine,mitoguazone, tiazofurin, ambamustine, bendamustine and DDS preparationsthereof.

Examples of the “anticancer antibiotic” that may be used includeactinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycinhydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicinhydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride,pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin,mithramycin, sarkomycin, carzinophilin, mitotane, zorubicinhydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride andDDS preparations (e.g., PEG liposomal doxorubicin) thereof.

Examples of the “plant-derived anticancer agent” that may be usedinclude etoposide, etoposide phosphate, vinblastine sulfate, vincristinesulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel,cabazitaxel, vinorelbine and DDS preparations thereof.

Examples of the “immunotherapeutic” that may be used include picibanil,Krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin,macrophage colony-stimulating factor, granulocyte colony-stimulatingfactor, erythropoietin, lymphotoxin, BCG vaccines, Corynebacteriumparvum, levamisole, polysaccharide K, procodazol, anti-CTLA4 antibodies(e.g., ipilimumab, tremelimumab), anti-PD-1 antibodies (e.g., nivolumab,pembrolizumab) and anti-PD-L1 antibodies.

The “cell growth factor” in the “agent inhibiting the effects of a cellgrowth factor and its receptor” can be any substance that promotes thegrowth of cells. Typical examples thereof include a factor that is apeptide having a molecular weight of 20,000 or smaller and exerts itseffects at a low concentration through binding to its receptor. Specificexamples of the cell growth factor that may be used include (1) EGF(epidermal growth factor) or a substance having activity substantiallyidentical thereto [e.g., TGFα], (2) insulin or a substance havingactivity substantially identical thereto [e.g., insulin, IGF(insulin-like growth factor)-1, IGF-2], (3) FGF (fibroblast growthfactor) or a substance having activity substantially identical thereto[e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10],and (4) other cell growth factors [e.g., CSF (colony stimulatingfactor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growthfactor), PDGF (platelet-derived growth factor), TGFβ (transforminggrowth factor β), HGF (hepatocyte growth factor), VEGF (vascularendothelial growth factor), heregulin, angiopoietin].

The “receptor of the cell growth factor” can be any receptor having theability to bind to any of the cell growth factor described above.Specific examples of the receptor that may be used include EGF receptor,heregulin receptor (e.g., HER3), insulin receptor, IGF receptor-1, IGFreceptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor,angiopoietin receptor (e.g., Tie2), PDGF receptor and the like.

Examples of the “agent inhibiting the effects of a cell growth factorand its receptor” that may be used include EGF inhibitors, TGFαinhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors,FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2inhibitors, NGF inhibitors, PDGF inhibitors, TGFβ inhibitors, HGFinhibitors, VEGF inhibitors, angiopoietin inhibitors, EGF receptorinhibitors, HER2 inhibitors, HER4 inhibitors, insulin receptorinhibitors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGFreceptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors,FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PKC inhibitors, Smoinhibitors, ALK inhibitors, ROR1 inhibitors, Trk inhibitors, Retinhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK(MEK1/2) inhibitors, MET inhibitors, CDK inhibitors, Akt inhibitors, ERKinhibitors, PI3K inhibitors and the like. More specific examples of theagent that may be used include anti-VEGF antibodies (e.g., bevacizumab,ramucirumab), anti-HER2 antibodies (e.g., trastuzumab, pertuzumab),anti-EGFR antibodies (e.g., cetuximab, panitumumab, matuzumab,nimotuzumab), anti-HGF antibodies, imatinib, erlotinib, gefitinib,sorafenib, sunitinib, dasatinib, lapatinib, vatalanib, ibrutinib,bosutinib, cabozantinib, crizotinib, alectinib, vismodegib, axitinib,motesanib, nilotinib,6-[4-(4-ethylpiperazin-1-ylmethyl)phenyl]-N-[1(R)-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine(AEE-788), vandetanib, temsirolimus, everolimus, enzastaurin,tozasertib, phosphoric acid2-[N-[3-[4-[5-[N-(3-fluorophenyl)carbamoylmethyl]-1H-pyrazol-3-ylamino]quinazolin-7-yloxy]propyl]-N-ethylamino]ethylester (AZD-1152),4-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazapin-2-ylamino]benzoicacid,N-[2-methoxy-5-[(E)-2-(2,4,6-trimethoxyphenyl)vinylsulfonylmethyl]phenyl]glycinesodium salt (ON-1910Na), volasertib, selumetinib, trametinib,N-[2(R),3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide(PD-0325901), bosutinib, regorafenib, afatinib, idelalisib, ceritinib,dabrafenib and the like.

In addition to the drugs described above, examples also includeL-asparaginase, L-arginase, arginine deiminase, aceglatone, procarbazinehydrochloride, protoporphyrin-cobalt complex salt, mercuryhematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan,topotecan, indotecan, indimitecan), topoisomerase II inhibitors (e.g.,sobuzoxane), differentiation inducers (e.g., retinoid, vitamins D),other angiogenesis inhibitors (e.g., fumagillin, shark extracts, COX-2inhibitors), α-blockers (e.g., tamsulosin hydrochloride), bisphosphonicacids (e.g., pamidronate, zoledronate), thalidomide, lenalidomide,pomalidomide, 5-azacytidine, decitabine, proteasome inhibitors (e.g.,bortezomib, carfilzomib, ixazomib), NEDD8 inhibitors (e.g.,pevonedistat), UAE inhibitors, PARP inhibitors (e.g., olaparib,niraparib, veliparib), antitumor antibodies such as anti-CD20 antibodies(e.g., rituximab, obinutuzumab), anti-CCR4 antibodies (e.g.,mogamulizumab) and the like, antibody-drug conjugates (e.g., trastuzumabemtansine, brentuximab vedotin) or the like.

Examples of the “enzyme replacement therapeutic” include agalsidase α,agalsidase β, olipudase alfa, alglucerase and the like.

Examples of the “Chaperone therapeutic” include migalastat and the like.

Examples of the “substrate reduction therapeutic” include miglustat andthe like.

Examples of the “cyclodextrin preparation” include hydroxyprolyl-β,γ-cyclodextrin and the like.

Examples of the “gene therapy” include a treatment method which involvestransferring a vector of adeno-associated virus (AAV) or the like to anormal gene, and the like.

Examples of the “cell therapy” include a treatment method which involvestransplanting hematopoietic stem cell source such as a bone marrow stemcell, a peripheral blood stem cell or the like.

The combination of the compound of the present invention and theconcomitant drug can produce excellent effects such as: (1) the dose ofthe compound of the present invention or the concomitant drug can bereduced as compared with the administration of the compound of thepresent invention or the concomitant drug alone; (2) the concomitantdrug can be selected for combined use with the compound of the presentinvention according to the symptoms (mild, serious, etc.) of a patient;(3) the period of treatment can be set longer; (4) a sustainedtherapeutic effect can be achieved; (5) a synergistic effect can beobtained by the combined use of the compound of the present inventionand the concomitant drug; and the like.

Hereinafter, the combined use of the compound of the present inventionand the concomitant drug is referred to as the “combination drug of thepresent invention”.

For use of the combination drug of the present invention, the time ofadministration of the compound of the present invention and the time ofadministration of the concomitant drug are not limited, and the compoundof the present invention and the concomitant drug may be administeredsimultaneously or in a staggered manner to a recipient. In the case ofadministration in a staggered manner, the staggered manner differsdepending on active ingredients to be administered, a dosage form and anadministration method. In the case of first administering, for example,the concomitant drug, the compound of the present invention can beadministered within 1 minute to 3 days, preferably within 10 minutes to1 day, more preferably within 15 minutes to 1 hour, after theadministration of the concomitant drug. In the case of firstadministering the compound of the present invention, the concomitantdrug can be administered within 1 minute to 1 day, preferably within 10minutes to 6 hours, more preferably within 15 minutes to 1 hour, afterthe administration of the compound of the present invention. The dose ofthe concomitant drug can abide by a dose clinically used and can beappropriately selected according to a recipient, an administrationroute, a disease, a combination, etc.

Examples of the administration mode of the compound of the presentinvention and the concomitant drug used in combination include (1) theadministration of a single preparation obtained by simultaneouslyformulating the compound of the present invention and the concomitantdrug, (2) the simultaneous administration through the sameadministration route of two preparations obtained by separatelyformulating the compound of the present invention and the concomitantdrug, (3) the administration through the same administration route in astaggered manner of two preparations obtained by separately formulatingthe compound of the present invention and the concomitant drug, (4) thesimultaneous administration through different administration routes oftwo preparations obtained by separately formulating the compound of thepresent invention and the concomitant drug, and (5) the administrationthrough different administration routes in a staggered manner of twopreparations obtained by separately formulating the compound of thepresent invention and the concomitant drug (e.g., administration in theorder of the compound of the present invention and then the concomitantdrug, or in the reverse order).

The dose of the concomitant drug can be appropriately selected on thebasis of a dose clinically used. The mixing ratio between the compoundof the present invention and the concomitant drug can be appropriatelyselected according to a recipient, an administration route, a targetdisease, symptoms, a combination, etc. When the recipient is, forexample, a human, 0.01 to 100 parts by weight of the concomitant drugcan be used with respect to 1 part by weight of the compound of thepresent invention.

The compound of the present invention or the combination drug of thepresent invention can be further used in combination with a non-drugtherapy. Specifically, the compound of the present invention or thecombination drug of the present invention may be combined with anon-drug therapy, for example, (1) surgery, (2) induced hypertensionchemotherapy using angiotensin II or the like, (3) gene therapy, (4)thermotherapy, (5) cryotherapy, (6) laser cauterization or (7)radiotherapy.

The compound of the present invention or the combination drug of thepresent invention is used, for example, before or after the surgery orthe like or before or after treatment involving two or three of thesetherapies in combination to produce effects such as prevention ofdevelopment of resistance, prolonged disease-free survival, inhibitionof cancer metastasis or recurrence, life prolongation and the like.

Also, the treatment with the compound of the present invention or thecombination drug of the present invention may be combined withsupportive care [(i) the administration of an antibiotic (e.g., aβ-lactam antibiotic such as Pansporin and the like, a macrolideantibiotic such as clarithromycin and the like) against variousintercurrent infections, (ii) the administration of a high-calorieinfusion, an amino acid preparation or multivitamin for the improvementof malnutrition, (iii) the administration of morphine for pain relief,(iv) the administration of a drug improving adverse reactions such asnausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia,decreased hemoglobin concentration, alopecia, liver damage, kidneydamage, DIC, fever and the like and (v) the administration of a drug forinhibiting multidrug resistance of cancer, etc.].

The present invention will be described further specifically withreference to Examples, Test Examples and Formulation Examples givenbelow. However, the present invention is not intended to be limited bythem, and various changes or modifications may be made therein withoutdeparting from the scope of the present invention.

Examples

In Examples below, the term “room temperature” usually meansapproximately 10° C. to approximately 35° C. A ratio used for a mixedsolvent represents a volume ratio unless otherwise specified. %represents % by weight unless otherwise specified.

The term “NH” in silica gel column chromatography represents that anaminopropylsilane-bound silica gel was used. A ratio used for elutionsolvents represents a volume ratio unless otherwise specified.

In Examples below, the following abbreviations are used:

mp: melting point

MS: mass spectrum

M: molar concentration

CDCl₃: deuterated chloroform

DMSO-d₆: deuterated dimethyl sulfoxide

¹H NMR: proton nuclear magnetic resonance

LC/MS: liquid chromatograph-mass spectrometer

ESI: electrospray ionization

APCI: atmospheric pressure chemical ionization

DME: 1,2-dimethoxyethane

DMA: N,N-dimethylacetamide

DMF: N,N-dimethylformamide

HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HOBt: 1-hydroxybenzotriazole

DPPA: diphenylphosphorylazide

mCPBA: m-chloroperbenzoic acid

TBAF: tetra-n-butylammonium fluoride

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

THF: tetrahydrofuran

¹H NMR was measured by Fourier transform NMR. ACD/SpecManager (tradename) or the like was used in analysis. No mention was made about thevery broad peaks of protons of a hydroxy group, an amino group and thelike.

MS was measured by LC/MS. ESI or APCI was used as an ionization method.Data was indicated by actually measured values (found). In general,molecular ion peaks ([M+H]⁺, [M−H]⁻ and the like) are observed. Forexample, in the case of a compound having a tert-butoxycarbonyl group, afragment ion peak derived from the elimination of thetert-butoxycarbonyl group or the tert-butyl group is observed. In thecase of a compound having a hydroxy group, a fragment ion peak derivedfrom the elimination of H₂O may be observed. In the case of a salt, amolecular ion peak or fragment ion peak of a free form is usuallyobserved.

Example 1A2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamideA) Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate

To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (62 g) andpotassium carbonate (221 g) in DMF (700 mL), dimethyl sulfate (121 g)was added dropwise under ice cooling, and the mixture was stirred atroom temperature for 14 hours. The reaction mixture was poured to water,followed by extraction with ethyl acetate. The extract was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (30 g).

¹H NMR (400 MHz, CDCl₃) δ 4.01 (3H, s), 4.03 (3H, s), 8.18 (1H, s).

B) Methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate

To a solution of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (10g) in methanol (200 mL), palladium-carbon (10%) (2 g) was added, and themixture was stirred at room temperature for 6 hours in a hydrogenatmosphere (45 psi). Palladium-carbon was filtered off, and then, thefiltrate was concentrated to obtain the title compound (8.57 g).

¹H NMR (400 MHz, CDCl₃) δ 3.86 (3H, s), 3.92 (3H, s), 4.08 (2H, brs),6.96 (1H, s).

C) Methyl4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate

To a mixture of methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate (7.67g) and methyl acrylate (5.45 g), acetic acid (0.77 g) was added, and theresulting mixture was stirred at 135° C. for 1 hour under irradiationwith microwave. The reaction mixture was cooled to room temperature andthen diluted with ethyl acetate. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate and saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (6.76 g).

¹H NMR (400 MHz, CDCl₃) δ 2.61 (2H, t, J=6.8 Hz), 3.28-3.35 (2H, m),3.70 (3H, s), 3.87 (3H, s), 3.89 (3H, s), 5.03 (1H, t, J=6.4 Hz), 6.88(1H, s).

D) Methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate

A mixture of methyl4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate (1.2g), benzyl bromide (1.0 g) and potassium carbonate (1.4 g) in 2-butanone(20 mL) was stirred for 12 hours under reflux. The reaction mixture wascooled to room temperature, and then, the insoluble matter was filteredoff. The solvent in the filtrate was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (1.22 g).

¹H NMR (400 MHz, CDCl₃) δ 2.44 (2H, t, J=7.2 Hz), 3.31 (2H, t, J=7.2Hz), 3.55 (3H, s), 3.80 (3H, s), 3.87 (3H, s), 4.16 (2H, s), 6.97 (1H,s), 7.14-7.28 (5H, m).

E) Methyl4-benzyl-2-methyl-7-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine-6-carboxylate

To a solution of methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-3-carboxylate(1.22 g) in THF (20 mL), lithium bis(trimethylsilyl)amide (1 M solutionin THF) (6.3 mL) was added dropwise at −20° C., and the mixture wasstirred for 2 hours. A saturated aqueous solution of ammonium chloridewas poured to the reaction mixture, followed by extraction with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure to obtain the titlecompound (0.93 g).

¹H NMR (400 MHz, CDCl₃) δ 3.34 (1H, dd, J₁=4.2 Hz, J₂=11.4 Hz),3.50-3.62 (2H, m), 3.68 (3H, s), 3.80 (3H, s), 4.08 (2H, d, J=2.4 Hz),6.62 (1H, s), 7.21-7.34 (5H, m).

F) 4-Benzyl-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

A solution of methyl4-benzyl-2-methyl-7-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine-6-carboxylate(3.2 g) in 6 N hydrochloric acid (40 mL) was stirred for 2 hours underreflux. The reaction mixture was neutralized with a 2 N aqueous sodiumhydroxide solution, followed by extraction with ethyl acetate. Theextract was dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound (1.83g).

¹H NMR (400 MHz, CDCl₃) δ 2.69 (2H, t, J=6.8 Hz), 3.25 (2H, t, J=6.8Hz), 3.85 (3H, s), 4.12 (2H, s), 6.67 (1H, s), 7.28-7.41 (5H, m).

G) 2-Methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of4-benzyl-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(1.83 g) in methanol (50 mL), palladium-carbon (10%) (0.3 g) and aceticacid (50 mg) were added, and the mixture was stirred at room temperaturefor 12 hours in a hydrogen atmosphere. Palladium-carbon was filteredoff, and then, the filtrate was concentrated to obtain the titlecompound (0.73 g).

¹H NMR (400 MHz, CDCl₃) δ 2.64 (2H, t, J=6.8 Hz), 3.46-3.51 (2H, m),3.89 (3H, s), 6.93 (1H, s).

H)4-(3,4-Dimethoxybenzoyl)-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one (0.73 g) andtriethylamine (1.47 g) in THF (20 mL), 3,4-dimethoxybenzoyl chloride(1.16 g) was gradually added, and the mixture was stirred at roomtemperature for 18 hours. Ethyl acetate was added to the reactionmixture. The reaction mixture was washed with a saturated aqueoussolution of sodium carbonate and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (382 mg).

¹H NMR (400 MHz, CDCl₃) δ 2.81 (2H, t, J=6.4 Hz), 3.95 (3H, s), 3.98(3H, s), 4.03 (3H, s), 4.19 (2H, t, J=6.4 Hz), 6.95 (1H, d, J=8.8 Hz),7.10-7.17 (2H, m).

I)(3,4-Dimethoxyphenyl)(7-hydroxy-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone

To a solution of4-(3,4-dimethoxybenzoyl)-2-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(380 mg) in methanol (20 mL), sodium tetrahydroborate (137 mg) wasgradually added, and the mixture was stirred at room temperature for 1hour. Water was added to the reaction mixture, and the mixture wasfurther stirred for 30 minutes. After extraction with dichloromethane,the extract was washed with saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (384 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.85-2.00 (2H, m), 3.70-3.80 (2H, m), 3.78(3H, s), 3.86 (3H, s), 3.88 (3H, s), 4.68-4.74 (1H, m), 5.32 (1H, d,J=4.8 Hz), 7.05-7.14 (3H, m), 8.17 (1H, brs).

J)(7-Azido-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone

To a solution of(3,4-dimethoxyphenyl)(7-hydroxy-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone(384 mg) in toluene (10 mL) and dichloromethane (10 mL), DPPA (0.84 g)was added dropwise at 0° C. in a nitrogen atmosphere. After stirring for10 minutes, DBU (0.5 g) was added thereto, and the mixture was stirredat room temperature for 3 hours. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (330 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.91-2.02 (1H, m), 2.03-2.17 (1H, m),3.63-3.72 (1H, m), 3.85 (3H, s), 3.87 (3H, s), 3.87-3.91 (1H, m), 3.93(3H, s), 4.97 (1H, t, J=4.0 Hz), 7.05-7.23 (3H, m), 8.26 (1H, brs).

K)(7-Amino-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone

To a solution of(7-azido-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone(330 mg) in methanol (10 mL) and dichloromethane (3 mL),palladium-carbon (10%) (30 mg) was added, and the mixture was stirred atroom temperature for 5 hours in a hydrogen atmosphere. Palladium-carbonwas filtered off, and then, the filtrate was concentrated to obtain thetitle compound (295 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.76-1.90 (1H, m), 2.01-2.12 (1H, m), 2.48(2H, brs), 3.58-3.72 (2H, m), 3.77 (3H, s), 3.79 (3H, s), 3.82 (3H, s),4.15-4.21 (1H, m), 6.98-7.07 (3H, m), 8.14 (1H, brs).

L)2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

To a solution of(7-amino-2-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone(283 mg) and triethylamine (270 mg) in THF (15 mL) and dichloromethane(5 mL), 2-chlorobenzoyl chloride (188 mg) was gradually added under icecooling, and the mixture was stirred at room temperature for 1 hour.Dichloromethane was added to the reaction mixture. The reaction mixturewas washed with a saturated aqueous solution of sodium carbonate andsaturated brine and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to obtain the title compound (200 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.91-2.02 (1H, m), 2.05-2.16 (1H, m),3.70-3.90 (11H, m), 5.17-5.24 (1H, m), 7.00-7.10 (3H, m), 7.35-7.51 (4H,m), 8.17 (1H, brs), 8.84 (1H, d, J=8.0 Hz).

Example 2A2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamideA) Methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate

To a suspension of 4-nitro-1H-pyrazole-3-carboxylic acid (37 g) andpotassium carbonate (97.6 g) in DMF (600 mL), dimethyl sulfate (71.2 g)was added dropwise under ice cooling, and the mixture was stirred atroom temperature for 16 hours. The reaction mixture was poured to water,followed by extraction with ethyl acetate. The extract was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (8.62 g).

¹H NMR (400 MHz, CDCl₃) δ 4.02 (3H, s), 4.03 (3H, s), 8.01 (1H, s).

B) Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate

To a solution of methyl 1-methyl-4-nitro-1H-pyrazole-5-carboxylate (8.62g) in methanol (100 mL), palladium-carbon (10%) (0.86 g) was added, andthe mixture was stirred at room temperature for 4 hours in a hydrogenatmosphere (40 psi). Palladium-carbon was filtered off, and then, thefiltrate was concentrated to obtain the title compound (4.71 g).

¹H NMR (400 MHz, CDCl₃) δ 3.91 (3H, s), 4.03 (3H, s), 4.15 (2H, brs),7.07 (1H, s).

C) Methyl4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-5-carboxylate

To a mixture of methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (4.71g) and methyl acrylate (3.14 g), acetic acid (0.4 g) was added, and theresulting mixture was stirred at 165° C. for 1 hour under irradiationwith microwave. The reaction mixture was cooled to room temperature andthen diluted with ethyl acetate. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate and saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (2.25 g).

¹H NMR (400 MHz, CDCl₃) δ 2.61 (2H, t, J=6.4 Hz), 3.38-3.46 (2H, m),3.70 (3H, s), 3.89 (3H, s), 4.03 (3H, s), 5.04 (1H, brs), 7.06 (1H, s).

D) Methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-5-carboxylate

A mixture of methyl4-[(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-5-carboxylate(2.25 g), benzyl bromide (1.91 g) and potassium carbonate (2.58 g) in2-butanone (50 mL) was stirred for 16 hours under reflux. The reactionmixture was cooled to room temperature, and then, the insoluble matterwas filtered off. The solvent in the filtrate was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (2.38 g).

¹H NMR (400 MHz, CDCl₃) δ 2.51 (2H, t, J=7.5 Hz), 3.34 (2H, t, J=7.5Hz), 3.62 (3H, s), 3.89 (3H, s), 4.10 (3H, s), 4.21 (2H, s), 7.28-7.41(6H, m).

E) Methyl4-benzyl-1-methyl-7-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine-6-carboxylate

To a solution of methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1-methyl-1H-pyrazole-5-carboxylate(2.38 g) in THF (50 mL), lithium bis(trimethylsilyl)amide (1 M solutionin THF) (18 mL) was added dropwise at −20° C., and the mixture wasstirred for 2 hours. A saturated aqueous solution of ammonium chloridewas poured to the reaction mixture, followed by extraction with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure to obtain the titlecompound (2.13 g).

¹H NMR (400 MHz, CDCl₃) δ 3.37 (1H, dd, J₁=4.2 Hz, J₂=11.4 Hz), 3.51(1H, dd, J₁=4.2 Hz, J₂=8.4 Hz), 3.55-3.65 (1H, m), 3.74 (3H, s), 4.08(3H, s), 4.27 (2H, d, J=4.2 Hz), 7.01 (1H, s), 7.24-7.41 (5H, m).

F) 4-Benzyl-1-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

A solution of methyl4-benzyl-1-methyl-7-oxo-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine-6-carboxylate(2.13 g) in 6 N hydrochloric acid (20 mL) was stirred for hours underreflux. The reaction mixture was concentrated, and then, a saturatedaqueous solution of sodium carbonate was added to the residue, followedby extraction with ethyl acetate. The extract was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to obtain the title compound (290 mg).

¹H NMR (400 MHz, CDCl₃) δ 2.57 (2H, t, J=7.2 Hz), 3.21 (2H, t, J=7.2Hz), 4.07 (3H, s), 4.24 (2H, s), 7.00 (1H, s), 7.24-7.41 (5H, m).

G) 1-Methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of4-benzyl-1-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(280 mg) in methanol (20 mL), palladium-carbon (10%) (30 mg) and aceticacid (50 mg) were added, and the mixture was stirred at room temperaturefor 16 hours in a hydrogen atmosphere. Palladium-carbon was filteredoff, and then, the filtrate was concentrated to obtain the titlecompound (140 mg).

¹H NMR (400 MHz, CDCl₃) δ 2.57 (2H, t, J=6.8 Hz), 3.50 (2H, t, J=6.8Hz), 3.85 (1H, brs), 4.06 (3H, s), 7.05 (1H, s).

H)4-(3,4-Dimethoxybenzoyl)-1-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of1-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one (570 mg) andtriethylamine (763 mg) in THF (20 mL), 3,4-dimethoxybenzoyl chloride(908 mg) was gradually added, and the mixture was stirred at roomtemperature for 2 hours. Ethyl acetate was added to the reactionmixture. The reaction mixture was washed with a saturated aqueoussolution of sodium carbonate and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (950 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 2.75 (2H, t, J=6.3 Hz), 3.78 (3H, s), 3.82(3H, s), 3.98-4.15 (5H, m), 7.00-7.10 (1H, m), 7.12-7.23 (2H, m),7.30-7.70 (1H, brs).

I)(3,4-Dimethoxyphenyl)(7-hydroxy-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone

To a solution of4-(3,4-dimethoxybenzoyl)-1-methyl-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(400 mg) in methanol (20 mL), sodium tetrahydroborate (144 mg) wasgradually added, and the mixture was stirred at room temperature for 1hour. Water was added to the reaction mixture, and the mixture wasfurther stirred for 30 minutes. After extraction with dichloromethane,the extract was washed with saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (418 mg).

¹H NMR (400 MHz, CDCl₃) δ 2.02-2.12 (2H, m), 2.28-2.36 (1H, m),3.50-3.65 (1H, m), 3.89 (6H, s), 3.92 (3H, s), 4.00-4.20 (1H, m),4.88-4.94 (1H, m), 6.87 (1H, d, J=8.0 Hz), 7.02-7.10 (2H, m).

J)(7-Azido-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone

To a solution of(3,4-dimethoxyphenyl)(7-hydroxy-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)methanone(412 mg) in toluene (10 mL) and dichloromethane (10 mL), DPPA (1.07 g)was added dropwise at 0° C. in a nitrogen atmosphere. After stirring for10 minutes, DBU (589 mg) was added thereto, and the mixture was stirredat room temperature for 3 hours. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (dichloromethane/methanol) to obtain the title compound(415 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.20 (2H, m), 3.18-3.30 (1H, m),3.40-3.60 (1H, m), 3.79 (3H, s), 3.82 (3H, s), 3.86 (3H, s), 5.19 (1H,t, J=4.0 Hz), 7.31 (1H, d, J=8.0 Hz), 7.05-7.14 (2H, m).

K)(7-Amino-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone

To a solution of(7-azido-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone(415 mg) in methanol (20 mL), palladium-carbon (10%) (40 mg) was added,and the mixture was stirred at room temperature for 3 hours in ahydrogen atmosphere. Palladium-carbon was filtered off, and then, thefiltrate was concentrated to obtain the title compound (350 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.86-2.05 (2H, m), 3.15-3.30 (1H, m),3.60-3.75 (1H, m), 3.78 (3H, s), 3.81 (3H, s), 3.83 (3H, s), 4.00-4.04(1H, m), 7.00-7.08 (3H, m), 7.70-8.10 (1H, brs).

L)2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

To a solution of(7-amino-1-methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-b]pyridin-4-yl)(3,4-dimethoxyphenyl)methanone(340 mg) and triethylamine (325 mg) in THF (20 mL), 2-chlorobenzoylchloride (226 mg) was gradually added under ice cooling, and the mixturewas stirred at room temperature for 2 hours. Dichloromethane was addedto the reaction mixture. The reaction mixture was washed with asaturated aqueous solution of sodium carbonate and saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether anddichloromethane/methanol) and recrystallized from ethylacetate/petroleum ether to obtain the title compound (250 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.98-2.20 (2H, m), 3.57-3.72 (1H, m),3.74-3.83 (9H, m), 3.84-4.00 (1H, m), 5.38-5.45 (1H, m), 6.98-7.10 (3H,m), 7.35-7.52 (4H, m), 7.70-8.30 (1H, brs), 9.07 (1H, d, J=8.4 Hz).

Example 3A2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-yl)benzamideA) Methyl 3-(4-bromo-1-methyl-1H-pyrazol-3-ylamino)propanoate

A mixture of 4-bromo-1-methyl-1H-pyrazol-3-amine (3.50 g), methylacrylate (8 mL), 4-(dimethylamino)pyridine (0.49 g) and DMF (3 mL) wasstirred at 135° C. for 3 hours and 30 minutes under irradiation withmicrowave. Water and ethyl acetate were added to the reaction mixture toseparate an organic layer. The aqueous layer was subjected to extractionwith ethyl acetate. The combined extract was washed with saturated brineand dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (3.20 g).

MS: [M+H]⁺ 261.8.

B) Methyl 3-(benzyl(4-bromo-1-methyl-1H-pyrazol-3-yl)amino)propanoate

To a mixture of methyl3-(4-bromo-1-methyl-1H-pyrazol-3-ylamino)propanoate (6.0 g), potassiumcarbonate (4.7 g) and acetonitrile (50 mL), benzyl bromide (4.3 g) wasadded at room temperature, and the resulting mixture was stirredovernight at 70° C. The insoluble matter was filtered off, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/petroleumether) to obtain the title compound (7.3 g).

MS: [M+H]⁺ 351.8.

C) Methyl 3-(benzyl(4-cyano-1-methyl-1H-pyrazol-3-yl)amino)propanoate

A mixture of methyl3-(benzyl(4-bromo-1-methyl-1H-pyrazol-3-yl)amino)propanoate (6.0 g),copper(I) cyanide (12.2 g) and DMF (50 mL) was stirred overnight at 150°C. The insoluble matter was filtered off, and the filtrate was subjectedto extraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (4.0 g).

MS: [M+H]⁺ 299.0.

D) Methyl3-(benzyl(3-methoxy-3-oxopropyl)amino)-1-methyl-1H-pyrazole-4-carboxylate

A mixture of methyl3-(benzyl(4-cyano-1-methyl-1H-pyrazol-3-yl)amino)propanoate (4.0 g),potassium hydroxide (9.8 g), ethanol (4 mL) and water (40 mL) wasstirred at 100° C. for 48 hours. The reaction mixture was diluted to pH8 with 2 N hydrochloric acid and concentrated under reduced pressure. Toa mixture of the residue, potassium carbonate (7.4 g) and DMF (50 mL),iodomethane (9.5 g) was added, and the resulting mixture was stirredovernight at 50° C. The insoluble matter was filtered off, and thefiltrate was diluted with water, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (3.3 g).

MS: [M+H]⁺ 331.9.

E) 7-Benzyl-2-methyl-6,7-dihydro-2H-pyrazolo[3,4-b]pyridin-4(5H)-one

To a solution of methyl3-(benzyl(3-methoxy-3-oxopropyl)amino)-1-methyl-1H-pyrazole-4-carboxylate(2.8 g) in THF (20 mL), a 1 M solution of sodiumbis(trimethylsilyl)amide in THF (15.1 mL) was added at −5° C., and themixture was stirred at the same temperature as above for 40 minutes. Thereaction mixture was diluted with a saturated aqueous solution ofammonium chloride, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Amixture of the residue, sodium hydroxide (1.5 g), THF (20 mL) and water(20 mL) was stirred at 70° C. for 6 hours. The reaction mixture wasdiluted to pH 9 with 1 N hydrochloric acid, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (1.2 g).

MS: [M+H]⁺ 242.0.

F) 7-Benzyl-2-methyl-6,7-dihydro-2H-pyrazolo[3,4-b]pyridin-4(5H)-oneoxime

A mixture of7-benzyl-2-methyl-6,7-dihydro-2H-pyrazolo[3,4-b]pyridin-4(5H)-one (1.2g), sodium acetate (1.7 g), hydroxylamine hydrochloride (1.4 g) andethanol (15 mL) was stirred overnight under conditions of heating toreflux. The reaction mixture was concentrated under reduced pressure,and the residue was diluted to pH 9 with a saturated aqueous solution ofsodium carbonate. The resulting precipitate was collected by filtrationto obtain the title compound (1.0 g).

MS: [M+H]⁺ 257.0.

G)7-Benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-amine

A mixture of7-benzyl-2-methyl-6,7-dihydro-2H-pyrazolo[3,4-b]pyridin-4(5H)-one oxime(872 mg), Raney nickel (1.6 g) and methanol (15 mL) was stirredovernight at 40° C. in a hydrogen atmosphere. The insoluble matter wasfiltered off, and the filtrate was concentrated under reduced pressureto obtain the title compound (800 mg).

MS: [M+H]⁺ 243.0.

H) tert-Butyl7-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate

To a solution of7-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-amine(800 mg) in dichloromethane (12 mL), triethylamine (668 mg) anddi-tert-butyl dicarbonate (864 mg) were added at room temperature. Afterstirring at the same temperature as above for 2 hours, the reactionmixture was diluted with water, followed by extraction withdichloromethane. The extract was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (715 mg).

MS: [M+H]⁺ 343.0.

I) tert-Butyl2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate

A mixture of tert-butyl7-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate (698 mg), 10% palladium-carbon (containing 50% water, 200 mg),acetic acid (0.5 mL) and THF (5 mL) was stirred at room temperature for3 days in a hydrogen atmosphere. The insoluble matter was filtered off,and the filtrate was diluted to pH 9 with a saturated aqueous solutionof sodium carbonate, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (480 mg).

MS: [M+H]⁺ 253.1.

J) tert-Butyl7-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate

To a mixture of tert-butyl2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate (139mg), triethylamine (89 mg) and dichloromethane (3 mL),3,4-dimethoxybenzoyl chloride (133 mg) was added under ice cooling, andthe resulting mixture was stirred overnight at room temperature. Thereaction mixture was diluted with ice-cold water, followed by extractionwith dichloromethane. The extract was washed with saturated brine anddried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by thin-layer silicagel column chromatography (ethyl acetate) to obtain the title compound(150 mg).

MS: [M+H]⁺ 416.9.

K)(4-Amino-2-methyl-5,6-dihydro-2H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone

tert-Butyl7-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-ylcarbamate(150 mg) was dissolved in dichloromethane (2 mL). To the solution, TFA(2 mL) was added, and the mixture was stirred at room temperature for 4hours. The reaction mixture was diluted with water and then diluted topH 9 with a saturated aqueous solution of sodium carbonate, followed byextraction with dichloromethane. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound (106mg).

MS: [M+H]⁺ 317.0.

L)2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-4-yl)benzamide

To a mixture of(4-amino-2-methyl-5,6-dihydro-2H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone (108 mg), pyridine (54 mg) and dichloromethane (1.5mL), 2-chlorobenzoyl chloride (77 mg) was added under ice cooling, andthe resulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was diluted with ice-cold water, followed by extractionwith dichloromethane. The extract was washed with saturated brine anddried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by reverse-phase HPLCto obtain the title compound (89 mg).

¹H NMR (400 MHz, CDCl₃) δ 2.11-2.17 (1H, m), 2.30-2.37 (1H, m), 3.72(3H, s), 3.79-3.85 (1H, m), 3.87 (3H, s), 3.92 (3H, s), 4.05-4.11 (1H,m), 5.33-5.37 (1H, m), 6.42 (1H, d, J=7.2 Hz), 6.82-6.84 (1H, m),7.13-7.15 (2H, m), 7.33-7.42 (4H, m), 7.69-7.71 (1H, m).

Example 17A2-Chloro-N-[4-(3,4-dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl]benzamideA) 5-Methyl-4-nitro-1,2-oxazole-3-carboxylic acid

To a solution of 5-methyl-1,2-oxazole-3-carboxylic acid (50.84 g) inconcentrated sulfuric acid (500 mL), sodium nitrate (50.99 g) wasgradually added at room temperature. The reaction mixture was stirred at50° C. for 16 hours. After cooling to room temperature, the reactionsolution was gradually added to ice, followed by extraction with ethylacetate. The extract was washed with water and saturated brine and thendried over anhydrous sodium sulfate to obtain the title compound (51.6g).

¹H NMR (400 MHz, DMSO-d₆) δ 2.28 (3H, s), 10.66 (1H, brs).

B) Methyl 5-methyl-4-nitro-1,2-oxazole-3-carboxylate

To a solution of 5-methyl-4-nitro-1,2-oxazole-3-carboxylic acid (40 g)in methanol (900 mL), thionyl chloride (80 mL) was added dropwise underice cooling. The reaction solution was stirred at room temperature for 3days, and then, methanol was distilled off under reduced pressure. Ethylacetate was added to the residue, and the mixture was washed withsaturated brine. The reaction mixture was dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (44.22 g).

¹H NMR (300 MHz, CDCl₃) δ2.86 (3H, s), 4.04 (3H, s).

C) Methyl 4-amino-5-methyl-1,2-oxazole-3-carboxylate

To a solution of ammonium chloride (55.7 g) in water (400 mL), asolution of methyl 5-methyl-4-nitro-1,2-oxazole-3-carboxylate (13 g) inmethanol (100 mL) was added. A zinc powder (54.5 g) was gradually addedto the reaction mixture under ice cooling, and the mixture was thenstirred at 5° C. for 1.5 hours. The insoluble matter was filtered off,and the filtrate was subjected to extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure to obtain the title compound (9.47 g).

¹H NMR (300 MHz, CDCl₃) δ 1.55 (2H, brs), 2.85 (3H, s), 4.03 (3H, s).

D) Methyl4-[(3-methoxy-3-oxopropyl)amino]-5-methyl-1,2-oxazole-3-carboxylate

To a mixture of methyl 4-amino-5-methyl-1,2-oxazole-3-carboxylate (27.8g) and methyl acrylate (55 mL), BF₃.Et₂O (12.64 g) was added dropwise atroom temperature, and the resulting mixture was then stirred at 80° C.for 9 hours. The reaction mixture was cooled to room temperature andthen diluted with ethyl acetate. The reaction mixture was washed with asaturated aqueous solution of sodium bicarbonate and saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (35.7 g).

¹H NMR (400 MHz, CDCl₃) δ 2.48 (3H, s), 2.54 (2H, d, J=6.4 Hz), 3.29(2H, d, J=6.8 Hz), 3.62 (3H, s), 3.69 (3H, s), 4.40 (1H, brs).

E) Methyl4-[(4-methoxybenzyl)(3-methoxy-3-oxopropyl)amino]-5-methyl-1,2-oxazole-3-carboxylate

A mixture of methyl4-[(3-methoxy-3-oxopropyl)amino]-5-methyl-1,2-oxazole-3-carboxylate(15.7 g), 4-methoxybenzyl bromide (19.5 g) and potassium carbonate(17.97 g) in 2-butanone (200 mL) was stirred for 6 hours under reflux.The reaction mixture was cooled to room temperature, and then, theinsoluble matter was filtered off. The solvent in the filtrate wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/petroleum ether) toobtain the title compound (12.02 g).

¹H NMR (400 MHz, CDCl₃) δ 2.05 (3H, s), 2.36 (2H, d, J=6.8 Hz), 3.36(2H, d, J=6.8 Hz), 3.62 (3H, s), 3.77 (3H, s), 4.00 (3H, s), 4.04 (2H,s), 6.77 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.8 Hz).

F) Methyl4-(4-methoxybenzyl)-3-methyl-7-oxo-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridine-6-carboxylate

A solution of methyl4-[(4-methoxybenzyl)(3-methoxy-3-oxopropyl)amino]-5-methyl-1,2-oxazole-3-carboxylate(12.02 g) in THF (50 mL) was added dropwise to a mixture of t-BuOK (9.31g) and THF (200 mL) at −20° C. The reaction mixture was stirred for 30minutes, and then, a saturated aqueous solution of ammonium chloride waspoured thereto, followed by extraction with ethyl acetate. The extractwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure to obtain the title compound (9.02 g).

¹H NMR (400 MHz, CDCl₃) δ 2.20 (3H, s), 3.79 (3H, s), 3.81 (3H, s), 3.90(2H, s), 4.09 (2H, s), 6.88 (2H, d, J=8.4 Hz), 7.18 (2H, d, J=8.4 Hz).

G)4-(4-Methoxybenzyl)-3-methyl-5,6-dihydro[1,2]oxazolo[4,3-b]pyridin-7(4H)-one

A mixture of methyl4-(4-methoxybenzyl)-3-methyl-7-oxo-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridine-6-carboxylate(9.02 g), aluminum oxide (100 g) and 1,4-dioxane (700 mL) was stirredfor 30 minutes under reflux. The reaction mixture was cooled to roomtemperature, and then, the insoluble matter was filtered off. Thesolvent in the filtrate was distilled off under reduced pressure toobtain the title compound (3.46 g).

MS: [M+H]⁺ 272.9.

H)4-(4-Methoxybenzyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-ol

To a solution of4-(4-methoxybenzyl)-3-methyl-5,-dihydro[1,2]oxazolo[4,3-b]pyridin-7(4H)-one(3.46 g) in methanol (100 mL), sodium tetrahydroborate (960 mg) wasgradually added, and the mixture was stirred at 15° C. for 1 hour. Waterwas added to the reaction mixture, and the mixture was further stirredfor 30 minutes. After extraction with ethyl acetate, the extract waswashed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to obtain the title compound (1.2 g).

¹H NMR (400 MHz, CDCl₃) δ 1.94-2.05 (2H, m), 2.38 (3H, s), 2.56 (1H, s),2.82-2.91 (1H, m), 3.03-3.11 (1H, m), 3.81 (3H, s), 4.11 (1H, d, J=14.8Hz), 4.24 (1H, d, J=14.8 Hz), 4.94-5.01 (1H, m), 6.88 (2H, d, J=8.0 Hz),7.22 (2H, d, J=8.0 Hz).

I) 2-Chlorobenzamide

To a 4 M solution of ammonia in THF (40 mL), a solution of2-chlorobenzoyl chloride (5 g) in THF (20 mL) was added dropwise underice cooling, and the mixture was stirred at room temperature for 2hours. Ethyl acetate was added to the reaction mixture. The reactionmixture was washed with water and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (4.6 g).

MS: [M+H]⁺ 155.7.

J) tert-Butyl (2-chlorobenzoyl)carbamate

To a suspension of 60% sodium hydride (in oil) (0.32 g) in THF (15 mL),a solution of 2-chlorobenzamide (0.62 g) in THF was added dropwise underice cooling, and the mixture was stirred at 15° C. for 20 minutes. Asolution of Boc₂O (0.87 g) in THF (15 mL) was slowly added to thereaction mixture, and the mixture was stirred at 15° C. for 30 minutes.A saturated aqueous solution of ammonium chloride was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas washed with saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/petroleum ether) to obtain the title compound (0.88 g).

¹H NMR (400 MHz, CDCl₃) δ 1.29 (9H, s), 7.14-7.31 (3H, m), 7.37 (1H, d,J=7.6 Hz), 7.64 (1H, brs).

K) tert-Butyl(2-chlorobenzoyl)[4-(4-methoxybenzyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl]carbamate

In a nitrogen atmosphere, to a solution of tert-butyl(2-chlorobenzoyl)carbamate (366 mg),4-(4-methoxybenzyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-ol(356 mg) and triphenylphosphine (3.75 g) in THF (20 mL), DEAD (2.26 g)was added dropwise at 0° C., and then, the mixture was stirred for 30minutes. The mixture was further stirred at room temperature for 16hours. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (ethylacetate/petroleum ether). The obtained residue was purified by HPLC toobtain the title compound (270 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.13 (9H, s), 2.06-2.15 (1H, m), 2.33 (3H, s),2.60-2.73 (1H, m), 2.88-2.98 (1H, m), 3.08-3.14 (1H, m), 3.82 (3H, s),4.03 (1H, d, J=14.4 Hz), 4.30 (1H, d, J=14.4 Hz), 5.84-5.94 (1H, m),6.89 (2H, d, J=8.8 Hz), 7.26-7.38 (5H, m), 7.51 (1H, d, J=6.0 Hz).

L) tert-Butyl(2-chlorobenzoyl)(3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl)carbamate

A solution of tert-butyl(2-chlorobenzoyl)[4-(4-methoxybenzyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl]carbamate(270 mg) and 1-chloroethyl chloroformate (2.27 g) in 1,2-dichloroethane(20 mL) was stirred for 2 hours under reflux. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolved inmethanol (20 mL). The solution was stirred for 2 hours under reflux. Thereaction mixture was concentrated under reduced pressure to obtain thetitle compound (260 mg).

MS: [M+H]⁺ 392.0.

M)2-Chloro-N-(3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl)benzamide

A mixture of tert-butyl(2-chlorobenzoyl)(3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl)carbamate(260 mg), trifluoroacetic acid (3 mL) and dichloromethane (12 mL) wasstirred at 15° C. for 3 hours. The solvent in the reaction mixture wasdistilled off under reduced pressure to obtain the title compound (240mg).

¹H NMR (400 MHz, CDCl₃) δ 1.90-2.03 (1H, m), 2.30 (3H, s), 2.52-2.61(1H, m), 2.93 (1H, brs), 3.25-3.40 (2H, m), 5.33-5.42 (1H, m), 6.68 (1H,brs), 7.30-7.44 (3H, m), 7.69-7.74 (1H, m).

N)2-Chloro-N-[4-(3,4-dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl]benzamide

To a solution of2-chloro-N-(3-methyl-4,5,6,7-tetrahydro[1,2]oxazolo[4,3-b]pyridin-7-yl)benzamide(240 mg) and triethylamine (250 mg) in THF (15 mL), 3,4-dimethoxybenzoylchloride (198 mg) was gradually added under ice cooling, and the mixturewas stirred for 30 minutes. The solvent in the reaction mixture wasdistilled off under reduced pressure. The residue was purified by HPLCto obtain the title compound (75 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.96-2.10 (1H, m), 2.39 (3H, s), 2.50-2.60(1H, m), 3.78-3.88 (1H, m), 3.92 (3H, s), 3.94 (3H, s), 4.05-4.15 (1H,m), 5.35-5.44 (1H, m), 6.78 (1H, d, J=6.0 Hz), 6.91 (1H, d, J=8.4 Hz),7.12-7.21 (2H, m), 7.30-7.42 (3H, m), 7.71 (1H, d, J=7.6 Hz).

Example 18A2-Chloro-N-{4-(3,4-dimethoxybenzoyl)-1-[(3-methyloxetan-3-yl)methyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl}benzamide

A mixture of an isomer mixture of2-chloro-N-[4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl]benzamideand2-chloro-N-[4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl]benzamide(150 mg), 3-(chloromethyl)-3-methyloxetane (45.1 mg), potassiumcarbonate (94 mg) and DMF (10 mL) was stirred at 50° C. for 15 hours.Water was added to the reaction mixture, followed by extraction withethyl acetate. The extract was washed with saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate) to obtain the title compound (37mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (3H, s), 1.90-2.21 (2H, m), 3.54-3.75(1H, m), 3.77 (3H, s), 3.81 (3H, s), 3.83-3.98 (1H, m), 4.17-4.36 (4H,m), 4.62 (1H, d, J=5.7 Hz), 4.71 (1H, d, J=5.7 Hz), 5.26-5.42 (1H, m),6.98-7.11 (3H, m), 7.34-7.54 (4H, m), 8.03 (1H, brs), 9.10 (1H, d, J=8.7Hz).

Example 30A2-Chloro-N-[4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl]benzamideA) Ethyl (2E)-cyano({[(4-methylphenyl)sulfonyl]oxy}imino)acetate

To a solution of ethyl (2E)-cyano(hydroxyimino)acetate (41.63 g) andtriethylamine (45.53 g) in ethyl acetate (300 mL), p-toluenesulfonylchloride (57.2 g) was gradually added under ice cooling. The reactionmixture was stirred at room temperature for 2 hours. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure. Water (300 mL) was added to the residue, and the mixture wasstirred for 15 minutes. The deposited precipitate was filtered and driedunder reduced pressure to obtain the title compound (49.18 g).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (3H, t, J=7.2 Hz), 2.48 (3H, s), 4.41(2H, q, J=7.2 Hz), 7.41 (2H, d, J=8.0 Hz), 7.92 (2H, d, J=8.4 Hz).

B) Diethyl 4-amino-1,2-thiazole-3,5-dicarboxylate

A mixture of ethyl(2E)-cyano({[(4-methylphenyl)sulfonyl]oxy}imino)acetate (37.1 g) andethyl 2-mercaptoacetate (22.53 g) in ethanol, pyridine (12.36 g) wasadded dropwise such that the temperature of the solution was 35 to 40°C. The reaction solution was stirred at room temperature for 3 hours,then triethylamine (20 mL) was added thereto, and the mixture wasfurther stirred for 30 minutes. The reaction mixture was added to icewater, followed by extraction with ethyl acetate. The extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain the titlecompound (28.45 g).

¹H NMR (400 MHz, CDCl₃) δ 1.38 (3H, t, J=7.2 Hz), 1.45 (3H, t, J=7.2Hz), 4.36 (2H, q, J=7.2 Hz), 4.45 (2H, q, J=7.2 Hz), 6.49 (2H, brs).

C) 4-Amino-1,2-thiazole-3-carboxylic acid hydrochloride

A solution of diethyl 4-amino-1,2-thiazole-3,5-dicarboxylate (28.45 g)in concentrated hydrochloric acid (110 mL) was stirred for 4 hours underreflux. The reaction solution was cooled to room temperature and thenleft standing overnight. The deposited crystals were collected byfiltration, washed with acetone and then dried to obtain the titlecompound (11.79 g).

¹H NMR (400 MHz, D₂O) δ 8.89 (1H, s).

D) Methyl 4-amino-1,2-thiazole-3-carboxylate

To a solution of 4-amino-1,2-thiazole-3-carboxylic acid hydrochloride(23.4 g) in methanol (800 mL), thionyl chloride (30 mL) was addeddropwise under ice cooling. The reaction solution was stirred at roomtemperature for 2 days, and then, methanol was distilled off underreduced pressure. Ethyl acetate was added to the residue, and themixture was washed with saturated brine. The reaction mixture was driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain the title compound (17.1 g).

¹H NMR (400 MHz, CDCl₃) δ 3.97 (3H, s), 4.93 (2H, brs), 7.56 (1H, s).

E) Methyl 4-[(3-methoxy-3-oxopropyl)amino]-1,2-thiazole-3-carboxylate

To a mixture of methyl 4-amino-1,2-thiazole-3-carboxylate (18.2 g) andmethyl acrylate (18 mL), acetic acid (0.69 g) was added, and the mixturewas stirred at 190° C. for 1.5 hours under irradiation with microwave.The reaction mixture was cooled to room temperature and then dilutedwith ethyl acetate. The reaction mixture was washed with a saturatedaqueous solution of sodium carbonate and saturated brine and then driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (5.6 g).

¹H NMR (400 MHz, CDCl₃) δ 2.68 (2H, t, J=6.8 Hz), 3.48 (2H, t, J=5.6Hz), 3.73 (3H, s), 3.98 (3H, s), 6.31 (1H, brs), 7.40 (1H, s).

F) Methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1,2-thiazole-3-carboxylate

A mixture of methyl4-[(3-methoxy-3-oxopropyl)amino]-1,2-thiazole-3-carboxylate (5.63 g),benzyl bromide (5.93 g) and potassium carbonate (6.36 g) in 2-butanone(100 mL) was stirred for 8 hours under reflux. The reaction mixture wascooled to room temperature, and then, the insoluble matter was filteredoff. The solvent in the filtrate was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (6.43 g).

¹H NMR (300 MHz, CDCl₃) δ 2.55 (2H, t, J=7.5 Hz), 3.43 (2H, t, J=7.5Hz), 3.61 (3H, s), 3.99 (3H, s), 4.29 (2H, s), 7.24-7.38 (5H, m), 7.95(1H, s).

G) Methyl4-benzyl-7-oxo-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridine-6-carboxylate

A solution of methyl4-[benzyl(3-methoxy-3-oxopropyl)amino]-1,2-thiazole-3-carboxylate (6.45g) in THF (20 mL) was added dropwise to a mixture of t-BuOK (4.33 g) andTHF (80 mL) at −20° C. The reaction mixture was stirred for 50 minutes,and then, a saturated aqueous solution of ammonium chloride was pouredthereto, followed by extraction with ethyl acetate. The extract wasdried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure to obtain the title compound (6.12 g).

¹H NMR (400 MHz, CDCl₃) δ 3.73 (3H, s), 4.09 (2H, s), 4.21 (2H, s), 6.92(1H, s), 7.20-7.38 (5H, m), 11.76 (1H, s).

H) 4-Benzyl-5,6-dihydro[1,2]thiazolo[4,3-b]pyridin-7(4H)-one

A mixture of methyl4-benzyl-7-oxo-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridine-6-carboxylate(6.12 g), aluminum oxide (90 g) and 1,4-dioxane (600 mL) was stirred for2 hours under reflux. The reaction mixture was cooled to roomtemperature, and then, the insoluble matter was filtered off. Thesolvent in the filtrate was distilled off under reduced pressure toobtain the title compound (3.66 g).

MS: [M+H]⁺ 244.9.

I) 4-Benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-ol

To a solution of4-benzyl-5,6-dihydro[1,2]thiazolo[4,3-b]pyridin-7(4H)-one (3.66 g) inmethanol (80 mL), sodium tetrahydroborate (1.14 g) was gradually added,and the mixture was stirred at 15° C. for 1 hour. Water was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas washed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (2.87 g).

¹H NMR (300 MHz, CDCl₃) δ 2.02-2.28 (2H, m), 2.88 (1H, brs), 3.10-3.22(1H, m), 3.25-3.39 (1H, m), 4.33 (2H, s), 4.92 (1H, t, J=5.1 Hz), 7.05(1H, s), 7.25-7.46 (5H, m).

J) 7-Azido-4-benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridine

To a solution of4-benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-ol (370 mg) intoluene (15 mL) and dichloromethane (15 mL), DPPA (1.24 g) was addeddropwise at 0° C. in a nitrogen atmosphere. After stirring for 30minutes, DBU (680 mg) was added thereto, and the mixture was stirred atroom temperature for 16 hours. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (390 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.94-2.02 (1H, m), 2.02-2.14 (1H, m),3.02-3.10 (1H, m), 3.17-3.25 (1H, m), 4.24 (1H, d, J=15.6 Hz), 4.30 (1H,d, J=15.2 Hz), 4.75 (1H, t, J=4.4 Hz), 7.06 (1H, s), 7.11-7.38 (5H, m).

K) 4-Benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-amine

To a solution of7-azido-4-benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridine (380 mg)in methanol (20 mL), palladium-carbon (10%) (40 mg) was added, and themixture was stirred at room temperature for 3 hours in a hydrogenatmosphere. Palladium-carbon was filtered off, and then, the filtratewas concentrated to obtain the title compound (280 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.65 (2H, brs), 1.76-1.90 (1H, m), 2.12-2.24(1H, m), 3.05-3.36 (2H, m), 4.00-4.06 (1H, m), 4.25 (2H, s), 6.95 (1H,s), 7.20-7.38 (5H, m).

L)N-(4-Benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl)-2-chlorobenzamide

To a solution of4-benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-amine (210 mg)and triethylamine (261 mg) in THF (10 mL), 2-chlorobenzoyl chloride (226mg) was gradually added under ice cooling, and the mixture was stirredat 15° C. for 1 hour. Dichloromethane was added to the reaction mixture.The reaction mixture was washed with a saturated aqueous solution ofsodium carbonate and saturated brine and then dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/petroleum ether) to obtain the title compound (210 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.00-2.15 (1H, m), 2.68-2.70 (1H, m),3.21-3.42 (2H, m), 4.34 (2H, s), 5.16-5.30 (1H, m), 6.89 (1H, d, J=5.7Hz), 7.05 (1H, s), 7.20-7.42 (8H, m), 7.72 (1H, d, J=2.1 Hz).

M)2-Chloro-N-(4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl)benzamide

A mixture ofN-(4-benzyl-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl)-2-chlorobenzamide(180 mg), aluminum chloride (313 mg) and toluene (10 mL) was stirred at50° C. for 4 hours. The reaction mixture was cooled to room temperature,and then, a saturated aqueous solution of sodium bicarbonate was addedto the reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and then dried over anhydroussodium sulfate, and the solvent was distilled off under reduced pressureto obtain the title compound (120 mg).

MS: [M+H]⁺ 293.8.

N)2-Chloro-N-[4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl]benzamide

To a solution of2-chloro-N-(4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b]pyridin-7-yl)benzamide(120 mg) and triethylamine (124 mg) in THF (10 mL), 3,4-dimethoxybenzoylchloride (98 mg) was gradually added at 15° C., and the mixture wasstirred for 30 minutes. The solvent in the reaction mixture wasdistilled off under reduced pressure, and the residue was purified byHPLC to obtain the title compound (30 mg).

¹H NMR (400 MHz, CDCl₃) δ 1.92-2.09 (1H, m), 2.74-2.84 (1H, m),3.84-3.90 (1H, m), 3.92 (3H, s), 3.95 (3H, s), 4.09-4.20 (1H, m),5.22-5.37 (1H, m), 6.93 (1H, d, J=8.4 Hz), 7.03 (1H, d, J=5.6 Hz),7.05-7.13 (2H, m), 7.30-7.44 (3H, m), 7.72-7.80 (1H, m), 9.21 (1H, brs).

Example 36A2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamideA) Methyl 1-isopropyl-4-nitro-1H-pyrazole-5-carboxylate

A mixture of 4-nitro-1H-pyrazole-5-carboxylic acid (10 g), tosylic acidmonohydrate (0.605 g) and methanol (120 mL) was stirred overnight at 65°C. The solvent was distilled off under reduced pressure, and the residuewas diluted with an excessive amount of an aqueous potassium carbonatesolution, followed by extraction with ethyl acetate (200 mL). Theaqueous layer was adjusted to pH 7 to 8 using 6 N hydrochloric acid,followed by extraction with an ethyl acetate-tetrahydrofuran mixedsolution (3/1, v/v, 200 mL). The organic layers were combined, washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue wasdissolved in N,N′-dimethylformamide (200 mL). To the solution, sodiumhydride (60%, 3.06 g) was added in small portions under ice cooling.After stirring at the same temperature as above for 20 minutes, propyl2-iodide (19.1 mL) was added dropwise thereto over 20 minutes. Themixture was stirred at the same temperature as above for 1 hour and atroom temperature for 5 hours. The reaction mixture was cooled to 10° C.and diluted with water (500 mL), followed by extraction with ethylacetate (300 mL) twice. The extract was washed with a saturated aqueoussolution of sodium bicarbonate and saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (3.59g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.43 (6H, d, J=6.6 Hz), 3.99 (3H, s),4.64-4.79 (1H, m), 8.41 (1H, s).

B) Methyl 4-amino-1-isopropyl-1H-pyrazole-5-carboxylate

A mixture of methyl 1-isopropyl-4-nitro-1H-pyrazole-5-carboxylate (3.57g), 10% palladium-carbon (containing 50% water, 0.18 g) and methanol (60mL) was stirred at room temperature for 2 hours in a hydrogenatmosphere. The insoluble matter was filtered off through celite, andthe filtrate was concentrated under reduced pressure. The residue wasdiluted with ethyl acetate, washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (3.02 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (6H, d, J=6.6 Hz), 3.79 (3H, s), 5.00(2H, s), 5.21 (1H, dt, J=13.1, 6.5 Hz), 7.05 (1H, s).

C) Methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-isopropyl-1H-pyrazole-5-carboxylate

A mixture of methyl 4-amino-1-isopropyl-1H-pyrazole-5-carboxylate (2.92g), methyl acrylate (13.7 g), 4-(dimethylamino)pyridine (0.389 g) andN,N′-dimethylformamide (20 mL) was stirred at 100° C. for 3 days. Thereaction mixture was cooled to room temperature, and redundant methylacrylate was distilled off under reduced pressure. Benzyl bromide (2.84mL) and potassium carbonate (3.30 g) were added to the residue, and themixture was stirred at room temperature for 8 hours. The reactionmixture was diluted with water (200 mL), followed by extraction withethyl acetate (200 mL). The extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (4.34 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (6H, d, J=6.6 Hz), 2.40-2.47 (2H, m),3.22 (2H, t, J=7.3 Hz), 3.50 (3H, s), 3.80 (3H, s), 4.14 (2H, s),5.12-5.25 (1H, m), 7.17-7.26 (1H, m), 7.27-7.31 (4H, m), 7.41 (1H, s).

D) 4-Benzyl-1-isopropyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one

To a solution of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-isopropyl-1H-pyrazole-5-carboxylate(4.24 g) in tetrahydrofuran (80 mL), a 1.9 M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (6.83 mL) was added dropwiseat room temperature. After stirring at the same temperature as above for1 hour, a 1.9 M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (3.10 mL) was added thereto, and the mixture was furtherstirred for 30 minutes, followed by the addition of a 1.9 M solution ofsodium bis(trimethylsilyl)amide in tetrahydrofuran (1.86 mL). Afterstirring at the same temperature as above for 1 hour, a 2 M aqueoussodium hydroxide solution (59 mL) was added thereto, and the reactionmixture was stirred at 70° C. for 3 hours. The reaction mixture wasdiluted with water (150 mL), followed by extraction with ethyl acetate(150 mL+50 mL). The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure to obtain the title compound (2.89 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.33 (6H, d, J=6.6 Hz), 2.45-2.53 (2H, m),3.12-3.19 (2H, m), 4.30 (2H, s), 5.16 (1H, quin, J=6.6 Hz), 7.25-7.42(6H, m).

E)4-Benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of4-benzyl-1-isopropyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one(900 mg), pyridine (1.32 g), hydroxylamine hydrochloride (1.16 g) andethanol (20 mL) was stirred at 80 to 90° C. for 6 hours. The solvent wasdistilled off under reduced pressure. The reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. A mixture of the residue, Raneynickel (8 g) and methanol (20 mL) was stirred at room temperature for 2hours in a hydrogen atmosphere. The insoluble matter was filtered offthrough celite, and the celite was washed with methanol-water (3/1). Thefiltrate was concentrated under reduced pressure. The residue wasdiluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (643 mg).

MS: [M+H]⁺ 271.0.

F)N-(4-Benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-chlorobenzamide

To a solution of4-benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine(640 mg) in tetrahydrofuran (12 mL), triethylamine (0.66 mL) and2-chlorobenzoyl chloride (0.36 mL) were added at room temperature. Afterstirring at the same temperature as above for 1 hour, the reactionmixture was diluted with ethyl acetate and washed with a saturatedaqueous solution of sodium bicarbonate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (927 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.31-1.41 (6H, m), 1.87-2.07 (2H, m),2.74-2.97 (2H, m), 3.92 (1H, d, J=14.3 Hz), 4.23 (1H, d, J=14.3 Hz),4.36-4.46 (1H, m), 5.25-5.32 (1H, m), 7.00 (1H, s), 7.23-7.50 (9H, m),9.03 (1H, d, J=8.5 Hz).

G)2-Chloro-N-(1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

To a solution ofN-(4-benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-chlorobenzamide(900 mg) in acetonitrile (12 mL), 1-chloroethyl chloroformate (472 mg)was added at room temperature. The mixture was stirred at 80° C. for 1hour. The solvent was distilled off under reduced pressure, and methanol(5 mL) was added to the residue. The mixture was stirred at 70° C. for 1hour. The reaction mixture was diluted with a saturated aqueous solutionof sodium bicarbonate, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (416 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (6H, dd, J=6.5, 1.0 Hz), 1.78-1.92 (2H,m), 2.98-3.07 (2H, m), 4.39 (1H, dt, J=13.0, 6.6 Hz), 4.47-4.51 (1H, m),5.23-5.31 (1H, m), 6.91 (1H, s), 7.32-7.51 (4H, m), 9.01 (1H, d, J=8.7Hz).

H)2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

To a solution of2-chloro-N-(1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide(300 mg) in pyridine (5 mL), 3,4-dimethoxybenzoyl chloride (283 mg) wasadded at room temperature. After stirring at the same temperature asabove for 1 hour, the reaction mixture was diluted with a saturatedaqueous solution of sodium bicarbonate, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and added to ethyl acetate-hexane.The deposit was collected by filtration to obtain the title compound(387 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.41 (6H, d, J=6.4 Hz), 1.94-2.20 (2H, m),3.57-3.98 (8H, m), 4.45-4.58 (1H, m), 5.38-5.49 (1H, m), 6.97-7.08 (3H,m), 7.34-7.53 (4H, m), 7.99 (1H, brs), 9.12 (1H, d, J=8.7 Hz).

Example 54AN-(3-Bromo-4-(3-chloro-4-methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazol[4,3-b]pyridin-7-yl)-2-chlorobenzamide

To a solution of2-chloro-N-(4-(3-chloro-4-methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide(95 mg) in ethyl acetate (2.0 mL), N-bromosuccinimide (38.7 mg) wasadded under ice cooling, and the mixture was stirred overnight at roomtemperature. The reaction mixture was diluted with a saturated aqueoussolution of sodium bicarbonate, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) and then crystallized fromethyl acetate/diisopropyl ether to obtain the title compound (37.5 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.04-2.20 (1H, m), 2.21-2.39 (1H, m), 3.70(1H, t, J=11.0 Hz), 3.85 (3H, s), 3.96 (3H, s), 4.08 (1H, d, J=16.0 Hz),5.51-5.66 (1H, m), 6.64 (1H, m), 6.95 (1H, d, J=8.5 Hz), 7.31-7.45 (3H,m), 7.53 (1H, d, J=8.3 Hz), 7.63-7.73 (2H, m).

Example 74A2-Chloro-N-((7S)-4-(3,4-dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

2-Chloro-N-(4-(3,4-dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide(400 mg) was fractionated by SFC (column: CHIRALCEL ODH, 20 mm ID×250 mmL, mobile phase: carbon dioxide/methanol=770/230), and a fraction havinga smaller retention time was concentrated under reduced pressure. Theresidue was added to ethyl acetate-hexane. The deposit was collected byfiltration to obtain the title compound (158 mg). Since the titlecompound of Example 75A was determined to be an R form, this compoundwas determined to be an S form.

¹H NMR (300 MHz, DMSO-d₆) δ 1.41 (6H, d, J=6.4 Hz), 1.95-2.19 (2H, m),3.56-3.95 (8H, m), 4.45-4.59 (1H, m), 5.39-5.47 (1H, m), 6.94-7.08 (3H,m), 7.34-7.54 (4H, m), 8.03 (1H, brs), 9.12 (1H, d, J=8.7 Hz).

>99.9% ee

Example 75A2-Chloro-N-((7R)-4-(3,4-dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

A fraction having a larger retention time in the optical resolutionoperation of Example 74A was concentrated under reduced pressure. Theresidue was added to ethyl acetate-hexane. The deposit was collected byfiltration to obtain the title compound (169 mg). The absolute structurewas determined to be an R form by single-crystal X-ray analysis.

¹H NMR (300 MHz, DMSO-d₆) δ 1.41 (6H, d, J=6.4 Hz), 1.95-2.20 (2H, m),3.54-3.94 (8H, m), 4.44-4.59 (1H, m), 5.37-5.49 (1H, m), 6.98-7.07 (3H,m), 7.35-7.53 (4H, m), 8.00 (1H, brs), 9.12 (1H, d, J=8.5 Hz).

>99.9% ee

Example 113A2-Chloro-N-(3-chloro-4-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

To a solution of2-chloro-N-(4-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide(200 mg) in DMF (2.0 mL), N-chlorosuccinimide (70.4 mg) was added atroom temperature, and the mixture was stirred overnight at the sametemperature as above. The reaction mixture was diluted with a saturatedaqueous solution of sodium bicarbonate, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) and reverse-phase HPLC andthen crystallized from THF/ethyl acetate/diisopropyl ether to obtain thetitle compound (16.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.90-2.04 (1H, m), 2.05-2.18 (1H, m), 3.76(6H, s), 3.81 (3H, s), 3.88-4.00 (2H, m), 5.29-5.50 (1H, m), 7.01 (1H,d, J=8.3 Hz), 7.07-7.24 (2H, m), 7.34-7.59 (4H, m), 9.13 (1H, d, J=8.5Hz).

Example 117A2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-b]pyridin-4-yl)benzamideA) Methyl 3-methyl-5-((phenoxycarbonyl)amino)isothiazole-4-carboxylate

To a solution of phenyl chloroformate (24.7 mL) in acetonitrile (300mL), potassium thiocyanate (19.1 g) was added at 0° C., and the mixturewas stirred at room temperature for 1 hour in a nitrogen atmosphere.Methyl 3-aminobut-2-enoate (22.6 g) was added thereto, and the mixturewas stirred at room temperature for 30 minutes. The reaction mixture wascooled to 0° C., then bromine (10.1 mL) was added thereto, and themixture was stirred at room temperature for 30 minutes. The reactionmixture was added to water/ethyl acetate. The insoluble matter wasfiltered off, and the filtrate was subjected to extraction with ethylacetate. The solvent was concentrated under reduced pressure. Theresidue was washed with ethyl acetate/diisopropyl ether to obtain thetitle compound (18.6 g).

MS: [M+H]⁺ 293.2.

B) Methyl 5-amino-3-methylisothiazole-4-carboxylate

To a mixture of methyl3-methyl-5-((phenoxycarbonyl)amino)isothiazole-4-carboxylate (36.3 g),water (25 mL) and N,N-dimethylformamide (250 mL), sodium carbonate (26.3g) was added, and the resulting mixture was stirred at 90° C. for 1hour. The reaction mixture was added to water, and the mixture wasfiltered through celite. The filtrate was subjected to extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (12.3g).

MS: [M+H]⁺ 173.2.

C) Methyl5-((3-methoxy-3-oxopropyl)amino)-3-methylisothiazole-4-carboxylate

To a mixed solution of methyl 5-amino-3-methylisothiazole-4-carboxylate(12.0 g), methyl acrylate (62.8 mL) and N,N-dimethylformamide (25 mL),N,N-dimethyl-4-aminopyridine (0.85 g) was added, and the mixture wasstirred at 100° C. for 15 hours in a nitrogen atmosphere. The reactionmixture was added to water, followed by extraction with ethyl acetate.The extract was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(7.4 g). methyl acrylate

MS: [M+H]⁺ 259.1.

D) Methyl5-(benzyl(3-methoxy-3-oxopropyl)amino)-3-methylisothiazole-4-carboxylate

To a mixture of methyl5-((3-methoxy-3-oxopropyl)amino)-3-methylisothiazole-4-carboxylate (6.10g), sodium iodide (0.35 g), cesium carbonate (23.1 g) and 2-butanone (47mL), (bromomethyl)benzene (8.4 mL) was added, and the resulting mixturewas refluxed for 5 hours and then cooled to room temperature.N,N-Dimethylacetamide (47 mL) and (bromomethyl)benzene (5.5 mL) wereadded to the reaction mixture, and the mixture was stirred at roomtemperature for 15 hours in a nitrogen atmosphere. The reaction mixturewas added to water, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (5.1g).

MS: [M+H]⁺ 349.3.

E) Methyl7-benzyl-3-methyl-4-oxo-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridine-5-carboxylate

To a solution of methyl5-(benzyl(3-methoxy-3-oxopropyl)amino)-3-methylisothiazole-4-carboxylate(4.40 g) in tetrahydrofuran (63 mL), a 1.9 M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran (13.3 mL) was added at 0° C.After stirring at the same temperature as above for 5 minutes, asaturated ammonium chloride solution was added thereto, followed byextraction with ethyl acetate. The extract was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (1.76 g).

MS: [M+H]⁺ 317.2.

F) 7-Benzyl-3-methyl-6,7-dihydroisothiazolo[5,4-b]pyridin-4(5H)-one

To a solution of methyl7-benzyl-3-methyl-4-oxo-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridine-5-carboxylate(1.73 g) in tetrahydrofuran (27 mL), a 2.0 M aqueous sodium hydroxidesolution (27 mL) was added at room temperature. The mixture was stirredat 60° C. for 3 d hours and cooled to room temperature, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (983 mg).

MS: [M+H]⁺ 259.1.

G) 7-Benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-ol

To a solution of7-benzyl-3-methyl-6,7-dihydroisothiazolo[5,4-b]pyridin-4(5H)-one (970mg) in methanol (15 mL), sodium borohydride (142 mg) was added at 0° C.,and the mixture was stirred at room temperature for 30 minutes in anitrogen atmosphere. The reaction mixture was poured to water, followedby extraction with ethyl acetate. The extract was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate) to obtainthe title compound (972 mg).

MS: [M+H]⁺ 261.2.

H)4-Azido-7-benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridine

To a solution of7-benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-ol (950mg) and DBU (1.64 mL) in toluene (15 mL), DPPA (2.35 mL) was addeddropwise at 0° C., and the mixture was stirred at room temperature for15 hours in a nitrogen atmosphere. The reaction mixture was purified bysilica gel column chromatography (ethyl acetate), and the solvent wasdistilled off under reduced pressure. The residue was purified again bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (833 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.76-2.02 (1H, m), 2.03-2.16 (1H, m), 2.38(3H, s), 3.02-3.39 (2H, m), 4.38 (2H, s), 4.50-4.66 (1H, m), 7.19-7.48(5H, m).

I) 7-Benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-amine

A mixture of4-azido-7-benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridine(820 mg), 10% palladium-carbon (containing 50% water, 82 mg) andmethanol (15 mL) was stirred at room temperature for 3 hours in ahydrogen atmosphere. The insoluble matter was filtered off, and thesolvent in the filtrate was distilled off under reduced pressure toobtain the title compound (742 mg).

MS: [M+H]⁺ 260.2.

J)N-(7-Benzyl-3-methyl-4,5,6,7-tetrahydroisothazolo[5,4-b]pyridin-4-yl)-2-chlorobenzamide

To a solution of7-benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-amine(730 mg) and triethylamine (0.79 mL) in tetrahydrofuran (10 mL),2-chlorobenzoyl chloride (0.38 mL) was added dropwise, and the mixturewas stirred at room temperature for 15 hours. The solvent in thereaction mixture was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (NH, ethyl acetate),and ethyl acetate was distilled off under reduced pressure. The residuewas purified again by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (459 mg).

MS: [M+H]⁺ 398.2.

K)2-Chloro-N-(3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-yl)benzamide

To a solution ofN-(7-benzyl-3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-yl)-2-chlorobenzamide(410 mg) in toluene (10 mL), aluminum chloride (687 mg) was added, andthe mixture was stirred at 60° C. for 2 hours. The reaction mixture waspurified by silica gel column chromatography (NH, ethylacetate/methanol), and the solvent was distilled off under reducedpressure. The residue was washed with ethyl acetate to obtain the titlecompound (251 mg).

MS: [M+H]⁺ 308.2.

L)2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-b]pyridin-4-yl)benzamide

To a solution of2-chloro-N-(3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-yl)benzamide(145 mg) in pyridine (2.0 mL), 3,4-dimethoxybenzoyl chloride (113 mg)was added dropwise, and the mixture was stirred at room temperature for30 minutes. The solvent in the reaction mixture was distilled off underreduced pressure. Then, the residue was purified by silica gel columnchromatography (NH, ethyl acetate), and the solvent was distilled offunder reduced pressure. The residue was purified again by silica gelcolumn chromatography (ethyl acetate/hexane), and the solvent wasdistilled off under reduced pressure. The obtained residue was washedwith ethyl acetate/hexane to obtain the title compound (23.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.94-2.22 (2H, m), 2.38 (3H, s), 3.69-3.97(7H, m), 4.02-4.17 (1H, m), 5.24-5.38 (1H, m), 6.94-7.24 (3H, m),7.28-7.59 (4H, m), 8.80 (1H, d, J=8.3 Hz).

Example 118A2-Chloro-N-(7-(3-chloro-4-methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-b]pyridin-4-yl)benzamide

To a mixture of2-chloro-N-(3-methyl-4,5,6,7-tetrahydroisothiazolo[5,4-b]pyridin-4-yl)benzamide(102 mg), 3-chloro-4-methoxybenzoic acid (186 mg), triethylamine (0.231mL) and N,N-dimethylformamide (2.0 mL), HATU (504 mg) was added, and theresulting mixture was stirred at room temperature for 18 hours. Thesolvent in the reaction mixture was distilled off under reducedpressure. Then, the residue was purified by silica gel columnchromatography (NH, ethyl acetate), and the solvent was distilled offunder reduced pressure. The residue was purified again by silica gelcolumn chromatography (ethyl acetate/hexane). The residue was added toethyl acetate/diisopropyl ether. The obtained deposit was collected byfiltration to obtain the title compound (49.5 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.01-2.22 (2H, m), 2.38 (3H, s), 3.69-4.18(5H, m), 5.09-5.51 (1H, m), 7.18-7.63 (6H, m), 7.68 (1H, d, J=2.1 Hz),8.77 (1H, d, J=8.3 Hz).

Example 126A4-Chloro-N-(4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamideA) Methyl 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole-5-carboxylate

To a mixture of methyl 4-nitro-1H-pyrazole-5-carboxylate (7.00 g),2,2-difluoroethanol (3.69 g), triphenylphosphine (14.0 g) and THF (120mL), a 1.9 M solution of diisopropyl azodicarboxylate in toluene (28.0mL) was added dropwise under ice cooling, and the reaction mixture wasstirred at room temperature for 3 hours in a nitrogen atmosphere. Thereaction mixture was diluted with water, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) and then washed with ethylacetate/diisopropyl ether to obtain the title compound (7.11 g).

¹H NMR (300 MHz, CDCl₃) δ 4.03 (3H, s), 4.75 (2H, td, J=13.2, 4.1 Hz),5.80-6.41 (1H, m), 8.10 (1H, s).

B) Methyl 4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate

A mixture of methyl1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole-5-carboxylate (7.10 g), 10%palladium-carbon (0.964 g) and methanol (200 mL) was stirred overnightat room temperature in a hydrogen atmosphere. The insoluble matter wasfiltered off, and the filtrate was concentrated under reduced pressure.The residue was washed with diisopropyl ether to obtain the titlecompound (4.62 g).

MS: [M+H]⁺ 205.9.

C) Methyl1-(2,2-difluoroethyl)-4-((3-methoxy-3-oxopropyl)amino)-1H-pyrazole-5-carboxylate

A mixture of methyl4-amino-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate (4.60 g), methylacrylate (20.2 mL), 4-(dimethylamino)pyridine (548 mg) and DMF (25 mL)was stirred at 100° C. for 2 days in a nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (2.46 g).

MS: [M+H]⁺ 291.9.

D) Methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate

To a mixture of methyl1-(2,2-difluoroethyl)-4-((3-methoxy-3-oxopropyl)amino)-1H-pyrazole-5-carboxylate(2.45 g), potassium carbonate (2.33 g) and DMF (30 mL), benzyl bromide(1.31 mL) was added, and the resulting mixture was stirred at roomtemperature for 3 hours. The reaction mixture was diluted with water,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (2.88 g).

MS: [M+H]⁺ 382.0.

E)4-Benzyl-1-(2,2-difluoroethyl)-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one

To a solution of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate(2.10 g) in THF (30 mL), a 1 M solution of sodiumbis(trimethylsilyl)amide in THF (8.26 mL) was added at room temperature,and the mixture was stirred at the same temperature as above for 2hours. A 2 M aqueous sodium hydroxide solution (27.5 mL) was addedthereto, and the reaction mixture was stirred at 70° C. for 3 hours. Thereaction mixture was neutralized with 2 M hydrochloric acid, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (910 mg).

MS: [M+H]⁺ 291.9.

F)4-Benzyl-1-(2,2-difluoroethyl)-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-oneoxime

A mixture of4-benzyl-1-(2,2-difluoroethyl)-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one(910 mg), pyridine (1.24 g), hydroxylamine hydrochloride (1.09 g) andethanol (10 mL) was stirred overnight at 90° C. The solvent in thereaction mixture was distilled off under reduced pressure, and theresidue was diluted with a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure to obtain thetitle compound (933 mg).

MS: [M+H]⁺ 306.9.

G)4-Benzyl-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of4-benzyl-1-(2,2-difluoroethyl)-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-oneoxime (930 mg), Raney nickel (10 g) and methanol (40 mL) was stirredovernight at room temperature in a hydrogen atmosphere. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to obtain the title compound (702 mg).

MS: [M+H]⁺ 292.9.

H) tert-Butyl(4-benzyl-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

To a solution of4-benzyl-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine(700 mg) and triethylamine (0.668 mL) in THF (7 mL), di-tert-butyldicarbonate (0.612 mL) was added dropwise at room temperature. Afterstirring at the same temperature as above for 2 hours, the reactionmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (826 mg).

MS: [M+H]⁺ 393.0.

I) tert-Butyl(1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(4-benzyl-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(825 mg), 10% palladium-carbon (containing 50% water, 112 mg), aceticacid (2.0 mL) and methanol (20 mL) was stirred at room temperature for 4hours in a hydrogen atmosphere. The insoluble matter was filtered off,and the filtrate was concentrated under reduced pressure. The residuewas washed with diisopropyl ether to obtain the title compound (625 mg).

MS: [M+H]⁺ 302.9.

J) tert-Butyl(4-(5-chloro-6-methoxynicotinoyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(310 mg), 5-chloro-6-methoxynicotinic acid (250 mg), HATU (585 mg),triethylamine (0.429 mL) and DMF (4.0 mL) was stirred at roomtemperature for 3 hours, and then, the reaction mixture was diluted withwater, followed by extraction with ethyl acetate. The extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to obtain the title compound (466 mg).

MS: [M+H]⁺ 472.0.

K)(7-Amino-1-(2,2-difluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5-chloro-6-methoxypyridin-3-yl)methanonedihydrochloride

tert-Butyl(4-(5-chloro-6-methoxynicotinoyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(466 mg) was dissolved in methanol (5 mL). To the solution, a 4 Msolution of hydrogen chloride in ethyl acetate (2.47 mL) was added, andthe mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the residue waswashed with ethyl acetate to obtain the title compound (422 mg).

MS: [M+H]⁺ 371.9.

L)4-Chloro-N-(4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

A mixture of(7-amino-1-(2,2-difluoroethyl)-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5-chloro-6-methoxypyridin-3-yl)methanonedihydrochloride (210 mg), 4-chloro-2-(trifluoromethyl)benzoic acid (138mg), HATU (269 mg), triethylamine (0.197 mL) and DMF (3.0 mL) wasstirred at room temperature for 4 hours, and then, the reaction mixturewas diluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)and then crystallized from ethyl acetate/diisopropyl ether to obtain thetitle compound (101 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.91-2.24 (2H, m), 3.70 (1H, d, J=10.4 Hz),3.77-3.96 (1H, m), 4.01 (3H, s), 4.38-4.70 (2H, m), 5.41 (1H, d, J=4.1Hz), 6.14-6.68 (1H, m), 7.62 (1H, d, J=8.3 Hz), 7.86 (1H, d, J=8.7 Hz),7.91 (1H, s), 8.04 (1H, s), 8.12 (1H, brs), 8.29 (1H, s), 9.22 (1H, d,J=7.9 Hz).

Example 132AN-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamideA) tert-Butyl(4-benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

To a solution of4-benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine(811 mg) and triethylamine (0.836 mL) in tetrahydrofuran (10 mL),di-tert-butyl dicarbonate (0.766 mL) was added at room temperature.After stirring at the same temperature as above for 1 hour, the reactionmixture was diluted with ethyl acetate and washed with water. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (1.06 g).

MS: [M+H]⁺ 371.0.

B) tert-Butyl(1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(4-benzyl-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(1.06 g), 10% palladium-carbon (containing 50% water, 319 mg), methanol(20 mL) and acetic acid (2 mL) was stirred overnight at room temperaturein a hydrogen atmosphere. The insoluble matter was filtered off, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with ethyl acetate/THF and washed with a saturated aqueoussolution of sodium bicarbonate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound (780mg).

MS: [M+H]⁺ 281.0.

C) tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(260 mg), 5,6-dimethoxynicotinic acid (221 mg), HATU (529 mg),triethylamine (0.388 mL) and DMF (4 mL) was stirred at room temperaturefor 4 hours, and then, the reaction mixture was diluted with water,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (359 mg).

MS: [M+H]⁺ 446.1.

D)(7-Amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride

tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(359 mg) was dissolved in methanol (3 mL). To the solution, a 4 Msolution of hydrogen chloride in ethyl acetate (2.02 mL) was added, andthe mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the residue waswashed with ethyl acetate to obtain the title compound (303 mg).

MS: [M+H]⁺ 346.0.

E)N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

A mixture of(7-amino-1-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride (300 mg), 2-(trifluoromethoxy)benzoic acid (192 mg),HATU (409 mg), triethylamine (0.300 mL) and DMF (3.0 mL) was stirred atroom temperature for 4 hours, and then, the reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) and thencrystallized from THF/ethyl acetate/diisopropyl ether to obtain thetitle compound (203 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, d, J=6.4 Hz), 1.48 (3H, d, J=6.4Hz), 2.25 (2H, d, J=3.8 Hz), 3.43-3.68 (1H, m), 3.91 (3H, s), 4.07 (3H,s), 4.14-4.33 (1H, m), 4.37-4.55 (1H, m), 5.48-5.70 (1H, m), 6.78 (1H,d, J=8.5 Hz), 7.23-7.27 (1H, m), 7.32 (1H, d, J=8.1 Hz), 7.41-7.49 (1H,m), 7.52-7.62 (1H, m), 7.89 (1H, d, J=1.9 Hz), 7.99 (1H, dd, J=7.7, 1.9Hz), 8.20 (1H, brs).

Example 133AN-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamideA) 4-Benzyl-1-methyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-oneoxime

A mixture of4-benzyl-1-methyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one (26g), pyridine (25.8 mL), hydroxylamine hydrochloride (11.0 g) and ethanol(150 mL) was stirred overnight in a nitrogen atmosphere under conditionsof heating to reflux. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (22 g).

MS: [M+H]⁺ 257.2.

B)4-Benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of4-benzyl-1-methyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one oxime(16 g), Raney nickel (10 g) and methanol (600 mL) was stirred overnightat room temperature in a hydrogen atmosphere. The insoluble matter wasfiltered off, and the filtrate was concentrated under reduced pressureto obtain the title compound (11 g).

MS: [M+H]⁺ 243.0.

C) tert-Butyl(4-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

To a solution of4-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine(3.40 g) and triethylamine (3.91 mL) in THF (50 mL), di-tert-butyldicarbonate (3.37 g) was added dropwise at room temperature. Afterstirring at the same temperature as above for 1 hour, the reactionmixture was diluted with water, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (4.70g).

MS: [M+H]⁺ 343.0.

D) tert-Butyl(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(4-benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(4.70 g), 10% palladium-carbon (containing 50% water, 1.46 g), aceticacid (5.0 mL) and methanol (100 mL) was stirred at room temperature for10 hours in a hydrogen atmosphere. The insoluble matter was filteredoff, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) and then washed with diisopropyl ether to obtain thetitle compound (2.06 g).

MS: [M+H]⁺ 253.0.

E) tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(260 mg), 5,6-dimethoxynicotinic acid (245 mg), HATU (588 mg),triethylamine (0.431 mL) and DMF (4 mL) was stirred at room temperaturefor 4 hours, and then, the reaction mixture was diluted with water,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (411 mg).

MS: [M+H]⁺ 418.0.

F)(7-Amino-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride

tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(411 mg) was dissolved in methanol (4 mL). To the solution, a 4 Msolution of hydrogen chloride in ethyl acetate (2.46 mL) was added, andthe mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure, and the residue waswashed with ethyl acetate to obtain the title compound (340 mg).

MS: [M+H]⁺ 318.0.

G)N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

A mixture of(7-amino-1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride (340 mg), 2-(trifluoromethoxy)benzoic acid (233 mg),HATU (497 mg), triethylamine (0.364 mL) and DMF (4.0 mL) was stirred atroom temperature for 4 hours, and then, the reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) and thencrystallized from THF/ethyl acetate/diisopropyl ether to obtain thetitle compound (184 mg).

¹H NMR (300 MHz, DMSO-d₆CDCl₃) δ 2.15-2.37 (2H, m), 3.43-3.65 (1H, m),3.82 (3H, s), 3.91 (3H, s), 4.07 (3H, s), 4.12-4.32 (1H, m), 5.49-5.68(1H, m), 6.75 (1H, d, J=8.1 Hz), 7.21-7.28 (1H, m), 7.31 (1H, s),7.40-7.50 (1H, m), 7.51-7.62 (1H, m), 7.88 (1H, d, J=1.9 Hz), 7.95-8.04(1H, m), 8.06-8.42 (1H, m).

Example 153A4-Chloro-N-(4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

-   -   A) Methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylate

Methyl 4-nitro-1H-pyrazole-5-carboxylate (15 g) was dissolved in DMF(250 mL). To the solution, sodium hydride (60%, 5.3 g) was added insmall portions under ice cooling. Ethyl iodide (20.5 g) was addedthereto, and the mixture was stirred at room temperature for 4 hours.The reaction mixture was added to water, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/petroleum ether) to obtain the titlecompound (3.7 g).

MS: [M+H]⁺ 200.1.

B) Methyl 4-amino-1-ethyl-1H-pyrazole-5-carboxylate

A mixture of methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylate (1.6 g),10% palladium-carbon (0.16 g) and methanol (50 mL) was stirred overnightat room temperature in a hydrogen atmosphere. The insoluble matter wasfiltered off, and the filtrate was concentrated under reduced pressureto obtain the title compound (1.2 g).

¹H NMR (500 MHz, CDCl₃) δ 1.36 (3H, t, J=7.0 Hz), 3.91 (3H, s), 4.44(2H, q, J=7.0 Hz), 7.09 (1H, s).

C) Methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-ethyl-1H-pyrazole-5-carboxylate

A mixture of methyl 4-amino-1-ethyl-1H-pyrazole-5-carboxylate (1.2 g),methyl acrylate (6.11 g), 4-(dimethylamino)pyridine (0.17 g) and DMF (60mL) was stirred at 120° C. for 3 days. The reaction mixture was cooledto room temperature, and redundant methyl acrylate was distilled offunder reduced pressure. Benzyl bromide (1.42 g) and potassium carbonate(2.28 g) were added to the residue, and the mixture was stirred at 80°C. for 1.5 hours. The reaction mixture was diluted with water, followedby extraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (2.0 g).

MS: [M+H]⁺ 346.0.

D) 4-Benzyl-1-ethyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one

To a solution of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-ethyl-1H-pyrazole-5-carboxylate(2.0 g) in THF (20 mL), a 2 M solution of sodiumbis(trimethylsilyl)amide in THF (4.4 mL) was added under ice cooling,and the mixture was stirred at the same temperature as above for 30minutes. A 6 M aqueous sodium hydroxide solution (16.9 mL) was addedthereto, and the reaction mixture was stirred overnight under refluxconditions. The reaction mixture was diluted with water, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain the title compound (2.2g).

MS: [M+H]⁺ 256.2.

E) 4-Benzyl-1-ethyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-oneoxime

A mixture of4-benzyl-1-ethyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one (3.5g), pyridine (3.25 g), hydroxylamine hydrochloride (1.42 g) and ethanol(60 mL) was stirred overnight at 90° C. The solvent was distilled offunder reduced pressure. The reaction mixture was diluted with asaturated aqueous solution of sodium bicarbonate, followed by extractionwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/petroleum ether) to obtain thetitle compound (3.2 g).

MS: [M+H]⁺ 271.3

F) 4-Benzyl-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine

A mixture of4-benzyl-1-ethyl-5,6-dihydro-1H-pyrazolo[4,3-b]pyridin-7(4H)-one oxime(2.8 g), Raney nickel (2.8 g) and methanol (100 mL) was stirredovernight at room temperature in a hydrogen atmosphere. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure to obtain the title compound (2.0 g).

¹H NMR (500 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.0 Hz), 1.65-1.69 (1H, m),1.74 (2H, brs), 1.84-1.92 (1H, m), 2.70-2.79 (2H, m), 3.91-3.95 (2H, m),4.00-4.13 (2H, m), 4.14 (1H, d, J=7.5 Hz), 6.89 (1H, s), 7.24-7.27 (1H,m), 7.31-7.36 (4H, m).

G) tert-Butyl(4-benzyl-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

To a solution of4-benzyl-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-amine(1.66 g) in THF (32.4 mL), triethylamine (1.81 mL) and di-tert-butyldicarbonate (1.58 mL) were added at room temperature. After stirring atthe same temperature as above for 1 hour, the reaction mixture wasdiluted with water, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (1.89 g).

¹H NMR (300 MHz, CDCl₃) δ 1.37-1.57 (12H, m), 1.93-2.13 (2H, m),2.53-2.63 (1H, m), 2.98 (1H, d, J=11.5 Hz), 3.93-4.13 (3H, m), 4.22 (1H,d, J=14.3 Hz), 4.83 (1H, s), 4.93 (1H, d, J=2.8 Hz), 7.25-7.38 (6H, m).

H) tert-Butyl(1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(4-benzyl-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(1.89 g), 10% palladium-carbon (containing 50% water, 282 mg), aceticacid (4.82 mL) and methanol (48.2 mL) was stirred at room temperaturefor 4 hours in a hydrogen atmosphere. The insoluble matter was filteredoff, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to obtain the title compound (1.22 g).

¹H NMR (300 MHz, CDCl₃) δ 1.40 (3H, t, J=7.3 Hz), 1.47 (9H, s),1.93-2.01 (2H, m), 3.00 (1H, d, J=5.7 Hz), 3.12 (1H, brs), 3.17-3.28(1H, m), 4.04 (2H, q, J=7.2 Hz), 4.88-4.99 (2H, m), 7.06 (1H, s).

I) tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

A mixture of tert-butyl(1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(500 mg), 5,6-dimethoxynicotinic acid (447 mg), HATU (1.07 g),triethylamine (0.785 mL) and DMF (9.39 mL) was stirred at roomtemperature for 3 hours, and then, the reaction mixture was diluted withwater, followed by extraction with ethyl acetate. The extract was washedwith saturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to obtain the title compound (601 mg).

MS: [M+H]⁺ 432.1.

J)(7-Amino-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride

tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(601 mg) was dissolved in methanol (6.96 mL). To the solution, a 4 Msolution of hydrogen chloride in ethyl acetate (3.48 mL) was added, andthe mixture was stirred overnight at room temperature. The reactionmixture was concentrated under reduced pressure to obtain the titlecompound (596 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (3H, t, J=7.2 Hz), 1.99-2.34 (2H, m),3.72-3.78 (1H, m), 3.83 (3H, s), 3.93 (3H, s), 4.23 (1H, brs), 4.72-4.87(1H, m), 7.39 (1H, d, J=1.7 Hz), 7.85 (1H, d, J=1.9 Hz), 8.57-8.83 (3H,m).

K)4-Chloro-N-(4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

A mixture of(7-amino-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride (180 mg), 4-chloro-2-(trifluoromethyl)benzoic acid (130mg), HATU (254 mg), triethylamine (0.248 mL) and DMF (2.23 mL) wasstirred overnight at room temperature, and then, the reaction mixturewas diluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)and then washed with ethyl acetate/diisopropyl ether to obtain the titlecompound (110 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (3H, t, J=7.2 Hz), 2.01 (2H, d, J=10.7Hz), 3.56-3.73 (1H, m), 3.83 (3H, s), 3.93 (4H, s), 4.06 (2H, q, J=7.1Hz), 5.35-5.42 (1H, m), 7.36 (1H, d, J=1.9 Hz), 7.60 (1H, d, J=8.3 Hz),7.81-7.86 (2H, m), 7.90 (1H, d, J=1.9 Hz), 9.25 (1H, d, J=8.1 Hz).

Example 155AN-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

A mixture of(7-amino-1-ethyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridin-4(5H)-yl)(5,6-dimethoxypyridin-3-yl)methanonedihydrochloride (180 mg), 2-(trifluoromethoxy)benzoic acid (119 mg),HATU (254 mg), triethylamine (0.248 mL) and DMF (2.23 mL) was stirredovernight at room temperature, and then, the reaction mixture wasdiluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)and then washed with ethyl acetate/diisopropyl ether to obtain the titlecompound (139 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (3H, t, J=7.2 Hz), 3.61-3.76 (1H, m),3.82 (3H, s), 3.92 (3H, s), 4.05 (2H, s), 5.37-5.48 (1H, m), 7.36 (1H,d, J=1.9 Hz), 7.46 (2H, d, J=1.4 Hz), 7.56-7.62 (2H, m), 7.82 (1H, d,J=1.9 Hz), 9.08-9.19 (1H, m).

Example 160A(N-((7S)-4-(3,4-Dimethoxybenzoyl)-1-(5-((3-(4,4-difluoro-5,7-dimethyl-3a-azonia-4-bora(IV)-4H-4a-aza-s-indacen-3-yl)propanoyl)amino)pentyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamideA) Methyl4-((3-methoxy-3-oxopropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

To a solution of methyl4-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate (6.2 g)and N,N-dimethyl-4-aminopyridine (300 mg) in DMF (50 mL), methylacrylate (24.79 mL) was added at room temperature, and the mixture wasstirred at 100° C. for 6 days. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (8.08g).

¹H NMR (300 MHz, CDCl₃) δ 1.53-1.74 (3H, m), 1.93-2.12 (3H, m), 2.63(2H, t, J=6.7 Hz), 3.34 (2H, q, J=6.6 Hz), 3.62-3.69 (1H, m), 3.70 (3H,s), 3.90 (3H, s), 4.07 (1H, dd, J=11.0, 2.3 Hz), 5.05 (1H, t, J=6.3 Hz),5.35 (1H, dd, J=8.7, 3.3 Hz), 7.13 (1H, s).

B) Methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate

To a solution of methyl4-((3-methoxy-3-oxopropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate(8.05 g) and potassium carbonate (7.15 g) in DMF (100 mL), benzylbromide (4.00 mL) was added at room temperature, and the reactionmixture was stirred overnight at room temperature. The solvent wasdistilled off under reduced pressure, and the residue was partitionedinto water and ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (10.18 g).

¹H NMR (300 MHz, CDCl₃) δ 1.56-1.74 (3H, m), 1.79-2.10 (3H, m), 2.48(2H, t, J=7.3 Hz), 3.34 (2H, t, J=7.3 Hz), 3.58 (3H, s), 3.60-3.72 (1H,m), 3.92 (3H, s), 4.03 (1H, d, J=11.1 Hz), 4.21 (2H, s), 5.34 (1H, d,J=9.0 Hz), 7.07-7.40 (6H, m).

C)4-Benzyl-2-(tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of methyl4-(benzyl(3-methoxy-3-oxopropyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate(10.1 g) in THF (150 mL), a 1.9 M solution of sodiumbis(trimethylsilyl)amide in THF (19.86 mL) was added at roomtemperature, and the reaction mixture was stirred at room temperaturefor 2 hours. A 2 M aqueous sodium hydroxide solution (126 mL) was addedto the reaction mixture at room temperature, and the mixture was stirredovernight at 70° C. The reaction solution was neutralized by theaddition of 2 M hydrochloric acid at room temperature, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue was washedwith diisopropyl ether to obtain the title compound (4.26 g).

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.72 (3H, m), 1.90-2.16 (3H, m),2.64-2.74 (2H, m), 3.13-3.25 (2H, m), 3.59-3.72 (1H, m), 3.90-4.05 (1H,m), 4.14 (2H, s), 5.30-5.44 (1H, m), 7.03 (1H, s), 7.21-7.49 (5H, m).

D)2-(Tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

A mixture of4-benzyl-2-(tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(4 g), 10% palladium-carbon (200 mg), acetic acid (10 mL) and methanol(100 mL) was stirred overnight at room temperature in a hydrogenatmosphere. The insoluble matter was filtered off, and the filtrate wasconcentrated under reduced pressure to obtain the title compound (4.06g).

¹H NMR (300 MHz, CDCl₃) δ 1.55-1.73 (3H, m), 1.90-2.15 (3H, m),2.62-2.72 (2H, m), 3.45-3.56 (2H, m), 3.61-3.76 (1H, m), 3.94-4.07 (1H,m), 5.33-5.43 (1H, m), 6.98 (1H, s), 7.19 (1H, s).

E)4-(3,4-Dimethoxybenzoyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To a solution of2-(tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(2.8 g) in pyridine (80 mL), 3,4-dimethoxybenzoyl chloride (3.81 g) wasadded at 0° C., and the mixture was stirred overnight at roomtemperature. The solvent was distilled off under reduced pressure, andthe residue was partitioned into 1 N hydrochloric acid and ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium carbonate and saturated brine and then dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (1.51 g).

¹H NMR (300 MHz, CDCl₃) δ 1.60-1.76 (3H, m), 1.94-2.03 (1H, m),2.06-2.20 (2H, m), 2.71-2.84 (2H, m), 3.62-3.76 (1H, m), 3.92 (3H, s),3.94 (3H, s), 3.99-4.07 (1H, m), 4.12-4.20 (2H, m), 5.47 (1H, dd, J=8.1,3.8 Hz), 6.88-6.96 (1H, m), 7.05-7.15 (2H, m), 8.13 (1H, brs).

F)4-(3,4-Dimethoxybenzoyl)-1,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one

To4-(3,4-dimethoxybenzoyl)-2-(tetrahydro-2H-pyran-2-yl)-2,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(1.5 g), a 2 M solution of hydrogen chloride in methanol (20 mL) wasadded at 0° C., and the mixture was stirred at room temperature for 2hours. The solvent was distilled off under reduced pressure, and theresidue was partitioned into ethyl acetate and a saturated aqueoussolution of sodium carbonate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. Diisopropyl ether wasadded to the residue, and the deposited solid was collected byfiltration to obtain the title compound (617.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.74 (2H, t, J=6.4 Hz), 3.78 (3H, s), 3.82(3H, s), 4.06 (2H, t, J=6.2 Hz), 7.01-7.10 (1H, m), 7.12-7.23 (2H, m),7.68 (1H, brs), 13.85 (1H, brs).

G) tert-Butyl(5-(4-(3,4-dimethoxybenzoyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate

To a mixture of4-(3,4-dimethoxybenzoyl)-1,4,5,6-tetrahydro-7H-pyrazolo[4,3-b]pyridin-7-one(300 mg), tert-butyl (5-hydroxypentyl)carbamate (0.30 mL),tributylphosphine (0.50 mL) and toluene (20 mL),(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (502 mg) was added atroom temperature, and the reaction mixture was stirred overnight at roomtemperature. The insoluble matter was filtered off, and then, thereaction mixture was diluted with water, followed by extraction withethyl acetate. The extract was washed with 1 M hydrochloric acid, asaturated aqueous solution of sodium carbonate and saturated brine anddried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (497mg).

¹H NMR (300 MHz, CDCl₃) δ 1.15-1.66 (15H, m), 2.74 (2H, t, J=6.5 Hz),3.65 (2H, q, J=6.0 Hz), 3.91 (3H, s), 3.94 (3H, s), 4.17 (2H, t, J=6.3Hz), 4.33-4.65 (3H, m), 6.90 (1H, d, J=8.7 Hz), 7.03-7.17 (2H, m), 7.43(1H, brs).

H) tert-Butyl(5-(4-(3,4-dimethoxybenzoyl)-7-hydroxy-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate

To a solution of tert-butyl(5-(4-(3,4-dimethoxybenzoyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate(484 mg) in methanol (10 mL), sodium borohydride (38 mg) was added at 0°C., and the mixture was stirred at room temperature for 3 hours. Anexcessive amount of 1 N hydrochloric acid was added thereto at 0° C. Thesolvent was distilled off under reduced pressure, and the residue waspartitioned into ethyl acetate and water. The organic layer was washedwith saturated brine and then dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure to obtain the titlecompound (423.9 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.31-1.66 (14H, m), 1.83-2.01 (1H, m),2.01-2.15 (1H, m), 2.98-3.20 (3H, m), 3.64 (1H, brs), 3.77 (1H, brs),3.89 (3H, s), 3.92 (3H, s), 4.04-4.23 (2H, m), 4.57 (1H, brs), 4.68 (1H,brs), 4.76-5.04 (1H, m), 6.88 (1H, d, J=8.3 Hz), 7.00-7.12 (2H, m),7.75-8.56 (1H, m).

I) tert-Butyl(5-(7-azido-4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate

To a mixed solution of tert-butyl(5-(4-(3,4-dimethoxybenzoyl)-7-hydroxy-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate(410 mg) in toluene (10 mL) and DMF (1 mL), DPPA (0.36 mL) and DBU (0.25mL) were added at room temperature, and the mixture was stirredovernight at 50° C. in an argon atmosphere. Water was added to thereaction solution, followed by extraction with ethyl acetate. Theextract was washed with a 10% aqueous citric acid solution, a saturatedaqueous solution of sodium carbonate and saturated brine and then driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(368.2 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.30-1.57 (15H, m), 1.78-2.00 (2H, m),2.09-2.35 (1H, m), 3.12 (2H, q, J=6.5 Hz), 3.55-3.71 (1H, m), 3.90 (3H,s), 3.93 (3H, s), 4.12 (2H, q, J=7.1 Hz), 4.57 (1H, brs), 4.67 (1H, t,J=3.6 Hz), 6.89 (1H, d, J=8.8 Hz), 6.96-7.16 (2H, m), 8.19 (1H, brs).

J) tert-Butyl(5-(7-amino-4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate

A mixture of tert-butyl(5-(7-azido-4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate(360 mg), 10% palladium-carbon (40 mg) and methanol (10 mL) was stirredovernight at room temperature in a hydrogen atmosphere. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure to obtain the title compound (313.6 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.27-2.00 (19H, m), 2.02-2.24 (1H, m), 3.11(2H, q, J=6.5 Hz), 3.51-3.72 (1H, m), 3.90 (3H, s), 3.92 (3H, s),4.03-4.31 (3H, m), 4.63 (1H, brs), 6.88 (1H, d, J=8.7 Hz), 7.02-7.15(2H, m), 8.19 (1H, brs).

K) tert-Butyl(5-(4-(3,4-dimethoxybenzoyl)-7-((2-(trifluoromethoxy)benzoyl)amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate

To a mixture of tert-butyl(5-(7-amino-4-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate(300 mg), 2-(trifluoromethoxy)benzoic acid (152 mg), WSC (143 mg), HOBt(125 mg) and DMF (10 mL), WSC (143 mg) was added at 0° C., and theresulting mixture was stirred at room temperature for 3 hours. Then, thesolvent was distilled off under reduced pressure. Ethyl acetate and asaturated aqueous solution of sodium carbonate were added to theresidue. The separated organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (410 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.25-1.51 (13H, m), 1.61-1.94 (3H, m), 2.22(2H, brs), 2.89 (2H, d, J=6.2 Hz), 3.55 (1H, brs), 3.90 (3H, s), 3.93(3H, s), 3.98-4.09 (2H, m), 4.53 (1H, brs), 5.48-5.66 (1H, m), 6.90 (1H,d, J=8.4 Hz), 7.02-7.11 (2H, m), 7.22 (1H, d, J=7.2 Hz), 7.30 (1H, d,J=8.2 Hz), 7.37-7.47 (1H, m), 7.49-7.60 (1H, m), 7.64-8.50 (2H, m).

L)(N-((7S)-4-(3,4-Dimethoxybenzoyl)-1-(5-((3-(4,4-difluoro-5,7-dimethyl-3a-azonia-4-bora(IV)-4H-4a-aza-s-indacen-3-yl)propanoyl)amino)pentyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

tert-Butyl(5-(4-(3,4-dimethoxybenzoyl)-7-((2-(trifluoromethoxy)benzoyl)amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl)pentyl)carbamate(161 mg) was fractionated by SFC (column: CHIRALPAK IB, 20 mm ID×250 mmL, mobile phase: carbon dioxide/methanol=860/140), and a fraction havinga smaller retention time was concentrated under reduced pressure. A 4 Msolution of hydrogen chloride in ethyl acetate (5 mL) was added to theresidue, and the mixture was stirred at room temperature for 3 hours.The reaction mixture was concentrated under reduced pressure, and theobtained residue was dissolved in DMF (3 mL).3-(4,4-Difluoro-5,7-dimethyl-3a-azonia-4-bora(IV)-4H-4a-aza-s-indacen-3-yl)propionicacid (29.3 mg), HOBt (20 mg) and triethylamine (0.042 mL) were dissolvedin DMF (3 mL). To the solution, WSC (23 mg) was added at 0° C. Thereaction mixture was stirred overnight at room temperature, and then,the solvent was distilled off under reduced pressure. The residue waspartitioned into ethyl acetate and water. The organic layer was washedwith saturated brine and then dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by reverse-phase HPLC to obtain the title compound (21.2 mg).

¹H NMR (300 MHz, METHANOL-d₄) δ 1.26-1.37 (3H, m), 1.41-1.56 (2H, m),1.76-1.98 (2H, m), 2.27 (4H, s), 2.49 (3H, s), 2.56 (2H, t, J=7.6 Hz),3.04-3.25 (5H, m), 3.55-3.77 (1H, m), 3.82 (3H, s), 3.87 (3H, s),4.02-4.17 (3H, m), 5.54 (1H, t, J=3.9 Hz), 6.20 (1H, s), 6.29 (1H, d,J=4.1 Hz), 6.97-7.01 (1H, m), 7.03 (1H, s), 7.08 (2H, dt, J=4.3, 2.2Hz), 7.36-7.43 (2H, m), 7.46 (1H, dd, J=7.5, 1.1 Hz), 7.52-7.63 (2H, m),7.78-7.96 (1H, m), 8.11 (1H, brs).

Example 162AN-((7S)-4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide(300 mg) was fractionated by SFC (column: CHIRALPAK AD, 50 mm ID×500 mmL, mobile phase: carbon dioxide/methanol=700/300), and a fraction havinga larger retention time was concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate/diisopropyl ether to obtainthe title compound (123 mg).

¹H NMR (300 MHz, DMSO-d₆CDCl₃) δ 1.42 (3H, d, J=6.4 Hz), 1.48 (3H, d,J=6.6 Hz), 2.16-2.30 (2H, m), 3.45-3.66 (1H, m), 3.91 (3H, s), 4.07 (3H,s), 4.12-4.35 (1H, m), 4.47 (1H, quin, J=6.6 Hz), 5.56-5.67 (1H, m),6.78 (1H, d, J=8.5 Hz), 7.24-7.28 (1H, m), 7.32 (1H, d, J=8.3 Hz),7.41-7.50 (1H, m), 7.52-7.61 (1H, m), 7.89 (1H, d, J=1.7 Hz), 8.00 (1H,dd, J=7.7, 1.9 Hz), 8.23 (1H, brs).

Example 165A4-Chloro-N-((7S)-4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

4-Chloro-N-(4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide(90.0 mg) was fractionated by SFC (column: CHIRALCEL OJ-H, 20 mm ID×250mm L, mobile phase: carbon dioxide/methanol=840/160), and a fractionhaving a larger retention time was concentrated under reduced pressure.The residue was crystallized from ethyl acetate/diisopropyl ether toobtain the title compound (31.2 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.44 (3H, t, J=7.3 Hz), 2.13-2.35 (2H, m),3.44-3.61 (1H, m), 3.90 (3H, s), 4.04-4.27 (6H, m), 5.42-5.57 (1H, m),6.27-6.45 (1H, m), 7.21-7.76 (1H, m), 7.48 (1H, d, J=8.1 Hz), 7.57-7.64(1H, m), 7.70-7.74 (1H, m), 7.83-7.86 (1H, m), 7.90-8.36 (1H, m).

Example 170A4-Chloro-N-((7S)-4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

4-Chloro-N-(4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide(1.08 g) was fractionated by SFC (column: CHIRALPAK AS-H, 20 mm ID×250mm L, mobile phase: carbon dioxide/methanol=840/160), and a fractionhaving a smaller retention time was concentrated under reduced pressure.The residue was crystallized from ethyl acetate/diisopropyl ether toobtain the title compound (457 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.09-2.37 (2H, m), 3.36-3.72 (1H, m),3.95-4.26 (4H, m), 4.35-4.61 (2H, m), 5.42-5.65 (1H, m), 5.90-6.45 (2H,m), 7.45-7.54 (1H, m), 7.56-7.65 (1H, m), 7.68-7.74 (1H, m), 7.78-7.85(1H, m), 7.86-8.55 (2H, m).

Example 171AN-((7S)-4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide(976 mg) was fractionated by SFC (column: CHIRALPAK AS-H, 20 mm ID×250mm L, mobile phase: carbon dioxide/methanol=880/120), and a fractionhaving a smaller retention time was concentrated under reduced pressure.The residue was crystallized from ethyl acetate/diisopropyl ether toobtain the title compound (380 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.12-2.35 (2H, m), 3.44-3.65 (1H, m), 3.82(3H, s), 3.91 (3H, s), 4.07 (3H, s), 4.12-4.36 (1H, m), 5.51-5.66 (1H,m), 6.77 (1H, d, J=8.3 Hz), 7.22-7.35 (2H, m), 7.40-7.49 (1H, m),7.51-7.60 (1H, m), 7.88 (1H, s), 7.93-8.45 (2H, m).

Example 172A2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-4-yl)benzamideA) 4-Bromo-1,3-dimethyl-1H-pyrazol-5-amine

To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (8.77 g) in ethylacetate (180 mL), N-bromosuccinimide (14.75 g) was added under icecooling, and the mixture was stirred at room temperature for 2 hours ina nitrogen atmosphere. The reaction mixture was diluted with a saturatedaqueous solution of sodium bicarbonate, followed by extraction withethyl acetate. The extract was washed with a saturated aqueous solutionof sodium bicarbonate and saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to obtain the title compound (12.6 g).

MS: [M+H]⁺ 189.9

B) 4-Bromo-N-(but-3-en-1-yl)-1,3-dimethyl-1H-pyrazol-5-amine

4-Bromo-1,3-dimethyl-1H-pyrazol-5-amine (12.3 g) was dissolved in DMF(120 mL). To the solution, sodium hydride (60%, 5.18 g) was added insmall portions at room temperature. After stirring at the sametemperature as above for 20 minutes, 4-bromobut-1-ene (16.4 mL) wasadded dropwise thereto, and the mixture was stirred overnight at thesame temperature as above in a nitrogen atmosphere. Water was added tothe reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to obtain the title compound (4.75 g).

MS: [M+H]⁺ 243.9

C)N-(4-Bromo-1,3-dimethyl-1H-pyrazol-5-yl)-N-(but-3-en-1-yl)-3,4-dimethoxybenzamide

4-Bromo-N-(but-3-en-1-yl)-1,3-dimethyl-1H-pyrazol-5-amine (4.73 g) wasdissolved in pyridine (40 mL). To the solution, 3,4-dimethoxybenzoylchloride (5.83 g) was added. The mixture was stirred at 90° C. for 5hours in a nitrogen atmosphere. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to obtain the title compound (6.52 g).

MS: [M+H]⁺ 408.0

D)(3,4-Dimethoxyphenyl)(1,3-dimethyl-4-methylene-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone

A mixture ofN-(4-bromo-1,3-dimethyl-1H-pyrazol-5-yl)-N-(but-3-en-1-yl)-3,4-dimethoxybenzamide(6.51 g), tri-ortho-tolylphosphine (728 mg), palladium(II) acetate (358mg), triethylamine (4.84 g) and acetonitrile (150 mL) was stirredovernight at 80° C. in a nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (1.75 g).

MS: [M+H]⁺ 328.0

E)7-(3,4-Dimethoxybenzoyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4(5H)-one

A mixed solution of(3,4-dimethoxyphenyl)(1,3-dimethyl-4-methylene-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone(1.73 g), sodium periodate (4.52 g) and osmium oxide (fixation catalystI) (403 mg) in acetonitrile (15 mL)-acetone (15 mL)-water (15 mL) wasstirred overnight at room temperature. The insoluble matter was filteredoff, and the filtrate was diluted with a saturated aqueous solution ofsodium thiosulfate, followed by extraction with ethyl acetate. Theextract was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to obtain the title compound (600 mg).

MS: [M+H]⁺ 330.0

F)(3,4-Dimethoxyphenyl)(4-(hydroxyimino)-1,3-dimethyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone

A mixture of7-(3,4-dimethoxybenzoyl)-1,3-dimethyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4(5H)-one(593 mg), pyridine (712 mg), hydroxylamine hydrochloride (626 mg) andethanol (10 mL) was stirred at 90° C. for 3 hours in a nitrogenatmosphere. The solvent was distilled off under reduced pressure, andthe residue was diluted with a saturated aqueous solution of sodiumbicarbonate, followed by extraction with THF/ethyl acetate. The extractwas washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain the title compound (577 mg).

MS: [M+H]⁺ 345.0

G)(4-Amino-1,3-dimethyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone

A mixture of(3,4-dimethoxyphenyl)(4-(hydroxyimino)-1,3-dimethyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone(563 mg), a 2 M solution of ammonia in methanol (8.17 mL), Raney nickel(1 g) and methanol (30 mL) was stirred overnight at room temperature ina hydrogen atmosphere. The insoluble matter was filtered off, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to obtain the title compound (445 mg).

MS: [M+H]⁺ 331.0

H)2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-4-yl)benzamide

To a solution of(4-amino-1,3-dimethyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone(441 mg) in pyridine (4 mL), 2-chlorobenzoyl chloride (280 mg) was addedat room temperature. After stirring at the same temperature as above for3 hours, the reaction mixture was concentrated under reduced pressure.The residue was diluted with a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)and then crystallized from methanol/ethyl acetate to obtain the titlecompound (255 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.07-2.21 (2H, m), 2.27 (3H, s), 3.50 (3H, s),3.64-3.80 (1H, m), 3.93 (3H, s), 3.95 (3H, s), 4.06-4.20 (1H, m),5.24-5.39 (1H, m), 6.24-6.40 (1H, m), 6.85-6.99 (1H, m), 7.23-7.28 (2H,m), 7.30-7.43 (3H, m), 7.62-7.75 (1H, m).

Example 178AN-((7S)-4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide(90.0 mg) was fractionated by SFC (column: CHIRALPAK AS-H, 20 mm ID×250mm L, mobile phase: carbon dioxide/methanol=860/140), and a fractionhaving a smaller retention time was concentrated under reduced pressure.The residue was crystallized from ethyl acetate/hexane to obtain thetitle compound (31.1 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7.3 Hz), 2.16-2.32 (2H, m),3.47-3.68 (1H, m), 3.91 (3H, s), 4.05-4.55 (6H, m), 5.52-5.65 (1H, m),6.78 (1H, d, J=8.3 Hz), 7.24-7.28 (1H, m), 7.29-7.35 (1H, m), 7.40-7.50(1H, m), 7.52-7.64 (1H, m), 7.89 (1H, d, J=1.9 Hz), 8.00 (1H, dd, J=7.7,1.9 Hz), 8.05-8.45 (1H, m).

Example 192AN-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamideA) tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate

To a solution of tert-butyl(4-(5,6-dimethoxynicotinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(400 mg) in acetonitrile (2.40 mL), a solution of N-bromosuccinimide(171 mg) in acetonitrile (2.40 mL) was added under ice cooling, and themixture was stirred at the same temperature as above for 1 hour and atroom temperature for 2 hours. The reaction mixture was concentratedunder reduced pressure and diluted with ethyl acetate. The reactionmixture was washed with water, a saturated aqueous solution of ammoniumchloride and saturated brine in this order and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressure.A mixture of the obtained residue (334 mg),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (24.6 mg),potassium carbonate (186 mg),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (169 mg) and DME (3.37 mL)was stirred at 110° C. for 1 hour under irradiation with microwave.2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (101.4 mg) was added tothe reaction mixture, and the mixture was stirred at 110° C. for 1 hourunder irradiation with microwave. The reaction mixture was purified bysilica gel column chromatography (NH, ethyl acetate/hexane) to obtainthe title compound (124 mg).

MS: [M+H]⁺ 432.1

B)N-(4-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

tert-Butyl(4-(5,6-dimethoxynicotinoyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)carbamate(124 mg) was dissolved in THF (1.44 mL). To the solution, TFA (1.07 mL)was added, and the mixture was stirred at room temperature for 4 days.The reaction mixture was concentrated under reduced pressure. A mixtureof the residue, 2-(trifluoromethoxy)benzoic acid (177 mg), HATU (163mg), triethylamine (0.239 mL) and DMF (2.0 mL) was stirred overnight atroom temperature in a nitrogen atmosphere. Then, the reaction mixturewas diluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)and then crystallized from THF/ethyl acetate/diisopropyl ether to obtainthe title compound (85.6 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.64-2.20 (4H, m), 2.21-2.36 (1H, m),3.59-3.79 (4H, m), 3.92 (3H, s), 4.07 (3H, s), 4.11-4.25 (1H, m),5.49-5.66 (1H, m), 6.71 (1H, d, J=8.5 Hz), 7.29-7.39 (2H, m), 7.46 (1H,dd, J=7.5, 1.1 Hz), 7.51-7.61 (1H, m), 7.93-8.01 (2H, m).

Example 193A2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrrazolo[3,4-b]pyridin-4-yl)benzamideA) 4-Bromo-N-(but-3-en-1-yl)-1-methyl-1H-pyrazol-5-amine

4-Bromo-1-methyl-1H-pyrazol-5-amine (5.00 g) was dissolved in DMF (80mL). To the solution, sodium hydride (60%, 1.70 g) was added in smallportions at room temperature. After stirring at the same temperature asabove for 20 minutes, 4-bromobut-1-ene (5.77 mL) was added dropwisethereto, and the mixture was stirred overnight at 50° C. in a nitrogenatmosphere. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to obtain the titlecompound (1.27 g).

MS: [M+H]⁺ 229.8

B)N-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-N-(but-3-en-1-yl)-3,4-dimethoxybenzamide

4-Bromo-N-(but-3-en-1-yl)-1-methyl-1H-pyrazol-5-amine (1.25 g) wasdissolved in pyridine (15 mL). To the solution, 3,4-dimethoxybenzoylchloride (1.64 g) was added, and the mixture was stirred overnight at90° C. in a nitrogen atmosphere. The reaction mixture was concentratedunder reduced pressure, and the residue was diluted with a saturatedaqueous solution of sodium bicarbonate, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(2.01 g).

MS: [M+H]⁺ 393.9

C)(3,4-Dimethoxyphenyl)(1-methyl-4-methylene-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone

A mixture ofN-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-(but-3-en-1-yl)-3,4-dimethoxybenzamide(2.00 g), tri-ortho-tolylphosphine (232 mg), palladium(II) acetate (114mg), triethylamine (1.54 g) and acetonitrile (50 mL) was stirredovernight at 80° C. in a nitrogen atmosphere. The reaction mixture wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane). The residue waswashed with diisopropyl ether to obtain the title compound (733 mg).

MS: [M+H]⁺ 314.0

D)7-(3,4-Dimethoxybenzoyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4(5H)-one

A mixed solution of(3,4-dimethoxyphenyl)(1-methyl-4-methylene-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone(730 mg), sodium periodate (1.99 g) and osmium oxide (fixation catalystI) (178 mg) in acetonitrile (5 mL)-acetone (5 mL)-water (5 mL) wasstirred at room temperature for 5 hours. The insoluble matter wasfiltered off, and the filtrate was diluted with a saturated aqueoussolution of sodium thiosulfate, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(195 mg).

MS: [M+H]⁺ 316.0

E)(3,4-Dimethoxyphenyl)(4-(hydroxyimino)-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone

A mixture of7-(3,4-dimethoxybenzoyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-4(5H)-one(193 mg), pyridine (242 mg), hydroxylamine hydrochloride (213 mg) andethanol (3 mL) was stirred overnight at 90° C. in a nitrogen atmosphere.The solvent was distilled off under reduced pressure, and the residuewas diluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to obtain the titlecompound (171 mg).

MS: [M+H]⁺ 331.0

F)(4-Amino-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone

A mixture of(3,4-dimethoxyphenyl)(4-(hydroxyimino)-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)methanone(170 mg), a 2 M solution of ammonia in methanol (2.57 mL), Raney nickel(1 g) and methanol (10 mL) was stirred at room temperature for 3 hoursin a hydrogen atmosphere. The insoluble matter was filtered off, thefiltrate was concentrated under reduced pressure to obtain the titlecompound (153 mg).

MS: [M+H]⁺ 317.0

G)2-Chloro-N-(7-(3,4-dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-4-yl)benzamide

To a solution of(4-amino-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-b]pyridin-7(4H)-yl)(3,4-dimethoxyphenyl)methanone(153 mg) in pyridine (3.0 mL), 2-chlorobenzoyl chloride (93 mg) wasadded at room temperature. After stirring at the same temperature asabove for 2 hours in a nitrogen atmosphere, the reaction mixture wasdiluted with a saturated aqueous solution of sodium bicarbonate,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)and then crystallized from ethyl acetate/diisopropyl ether to obtain thetitle compound (71.9 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.99-2.15 (1H, m), 2.17-2.33 (1H, m), 3.59(3H, s), 3.77-3.90 (1H, m), 3.92 (3H, s), 3.95 (3H, s), 4.03-4.16 (1H,m), 5.26-5.41 (1H, m), 6.38 (1H, d, J=7.2 Hz), 6.92 (1H, d, J=8.3 Hz),7.20-7.30 (2H, m), 7.30-7.43 (3H, m), 7.52 (1H, s), 7.64-7.72 (1H, m).

Example 201A2-Chloro-N-(7-chloro-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)benzamideA) N-(3-Chlorophenyl)-N-((4-methylphenyl)sulfonyl)-beta-alanine

A mixture of 3-chloroaniline (25.50 g), acrylic acid (13.7 mL) andtoluene (100 mL) was stirred at 110° C. for 16 hours. The reactionmixture was acidified with 1 N hydrochloric acid, and then, water andethyl acetate were added thereto to separate an organic layer. Theaqueous layer was subjected to extraction with ethyl acetate. Thecombined extracts were washed with water and saturated brine and driedover anhydrous magnesium sulfate, and then, the solvent was distilledoff under reduced pressure. A mixture of the residue, p-toluenesulfonylchloride (41.00 g), pyridine (35 mL) and toluene (200 mL) was stirred atroom temperature for 100 hours. The solvent was distilled off underreduced pressure, and then, the mixture was diluted with 1 Nhydrochloric acid. Ethyl acetate was added thereto to separate anorganic layer. The aqueous layer was subjected to extraction with ethylacetate. The combined extracts were washed with water and saturatedbrine and dried over anhydrous magnesium sulfate, and then, the solventwas distilled off under reduced pressure to obtain the title compound(59.80 g).

MS: [M+H]⁺ 353.9.

B) 7-Chloro-2,3-dihydroquinolin-4(1H)-one

To a solution ofN-(3-chlorophenyl)-N-((4-methylphenyl)sulfonyl)-beta-alanine (30.00 g)in THF (500 mL), a catalytic amount of DMF and oxalyl chloride (17.5 mL)were added at 0° C. After stirring at room temperature for 1 hour, thesolvent was distilled off under reduced pressure. The obtained solid wasdissolved in nitroethane (400 mL). To the solution, aluminum chloride(47.60 g) was added at 0° C., and then, the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was poured to ice, followedby extraction with ethyl acetate. The extract was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and then,the solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (7.60 g).

MS: [M+H]⁺ 182.0.

C) tert-Butyl 7-chloro-4-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylate

To a solution of 7-chloro-2,3-dihydroquinolin-4(1H)-one (7.60 g) in THF(100 mL), di-tert-butyl dicarbonate (10.1 mL) andN,N-dimethyl-4-aminopyridine (2.10 g) were added at room temperature.After stirring at the same temperature as above for 14 hours, thereaction mixture was concentrated under reduced pressure, and water wasadded thereto, followed by extraction with ethyl acetate. The extractwas washed with water and saturated brine and dried over anhydrousmagnesium sulfate. Then, the solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane). To a solution of the obtained oilin THF (150 mL) and methanol (75 mL), sodium borohydride (1.60 g) wasadded at 0° C. After stirring at the same temperature as above for 1hour, the mixture was further stirred at room temperature for 1 hour.Water was added to the reaction mixture, and then, the reaction mixturewas concentrated under reduced pressure, followed by extraction withethyl acetate. The extract was washed with water and saturated brine anddried over anhydrous magnesium sulfate, and then, the solvent wasdistilled off under reduced pressure to obtain the title compound (10.30g).

¹H NMR (300 MHz, CDCl₃) δ 1.54 (9H, s), 1.71-1.85 (1H, m), 1.86-2.12(1H, m), 3.47-3.75 (1H, m), 3.89-4.08 (1H, m), 4.65-4.78 (1H, m), 7.04(1H, dd, J=8.3, 2.1 Hz), 7.30 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=1.9 Hz).

D) tert-Butyl 4-amino-7-chloro-3,4-dihydroquinoline-1(2H)-carboxylatehydrochloride

To a solution of tert-butyl7-chloro-4-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylate (5.00 g) intoluene (100 mL), diphenylphosphorylazide (4.5 mL) anddiazabicycloundecene (3.1 mL) were added at room temperature. Afterstirring at the same temperature as above for 18 hours, the reactionmixture was diluted with water, followed by extraction with ethylacetate. The solvent was distilled off under reduced pressure, and then,the residue was purified by silica gel column chromatography (ethylacetate/hexane). A mixture of the obtained oil, triphenylphosphine (8.30g), THF (400 mL) and water (40 mL) was stirred at 100° C. for 2 hours.The reaction mixture was concentrated under reduced pressure, and waterwas added thereto, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and dried overanhydrous magnesium sulfate, and then, the solvent was distilled offunder reduced pressure. The residue was diluted with diethyl ether, anda 4 M solution of hydrogen chloride in ethyl acetate was added thereto,and the obtained precipitate was collected by filtration to obtain thetitle compound (2.50 g).

¹H NMR (300 MHz, CDCl₃) δ 1.49 (9H, s), 1.94-2.10 (1H, m), 2.10-2.24(1H, m), 3.59-3.77 (1H, m), 3.79-3.92 (1H, m), 4.49 (1H, brs), 7.22 (1H,dd, J=8.3, 2.3 Hz), 7.55 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=2.3 Hz), 8.60(3H, brs).

E) tert-Butyl7-chloro-4-((2-chlorobenzoyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate

A mixture of tert-butyl4-amino-7-chloro-3,4-dihydroquinoline-1(2H)-carboxylate hydrochloride(2.50 g), 2-chlorobenzoyl chloride (1.1 mL), triethylamine (2.5 mL) andTHF (50 mL) was stirred at room temperature for 2 hours. Then, thereaction mixture was concentrated under reduced pressure, and water wasadded thereto, followed by extraction with ethyl acetate. The extractwas washed with 1 N hydrochloric acid, a saturated aqueous solution ofsodium bicarbonate and saturated brine and dried over anhydrousmagnesium sulfate, and then, the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (3.10 g).

¹H NMR (300 MHz, CDCl₃) δ 1.55 (9H, s), 2.09-2.32 (2H, m), 3.65-3.81(1H, m), 3.87-4.03 (1H, m), 5.29-5.39 (1H, m), 6.39 (1H, d, J=7.5 Hz),7.04 (1H, dd, J=8.3, 2.3 Hz), 7.27-7.43 (4H, m), 7.67-7.75 (1H, m), 7.88(1H, d, J=2.1 Hz).

F) 2-Chloro-N-(7-chloro-1,2,3,4-tetrahydroquinolin-4-yl)benzamidehydrochloride

A mixture of tert-butyl7-chloro-4-((2-chlorobenzoyl)amino)-3,4-dihydroquinoline-1(2H)-carboxylate(3.10 g) and a 4 M solution of hydrogen chloride in ethyl acetate (20mL) was stirred at room temperature for 1 hour. Diethyl ether was addedto the reaction, and the mixture was stirred for 30 minutes. Theobtained precipitate was collected by filtration to obtain the titlecompound (2.40 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.87-1.98 (2H, m), 3.27 (2H, t, J=5.7 Hz),4.98-5.18 (1H, m), 6.46 (2H, brs), 6.54-6.66 (2H, m), 7.13 (1H, d, J=7.9Hz), 7.32-7.53 (4H, m), 8.82 (1H, d, J=8.3 Hz).

G)2-Chloro-N-(7-chloro-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)benzamide

To a solution of 3,4-dimethoxybenzoic acid (0.48 g) in THF (15 mL), acatalytic amount of DMF and oxalyl chloride (0.28 mL) were added. Themixture was stirred at room temperature for 1 hour, and then, thesolvent was distilled off under reduced pressure. To a suspension of theobtained solid in THF (15 mL),2-chloro-N-(7-chloro-1,2,3,4-tetrahydroquinolin-4-yl)benzamidehydrochloride (0.79 g) and triethylamine (0.69 mL) were added, and themixture was stirred at 50° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and water was added thereto,followed by extraction with ethyl acetate. The extract was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonateand saturated brine and dried over anhydrous magnesium sulfate, andthen, the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (0.89 g).

¹H NMR (300 MHz, CDCl₃) δ 2.08-2.25 (1H, m), 2.28-2.49 (1H, m),3.76-3.89 (1H, m), 3.84 (3H, s), 3.91 (3H, s), 4.00-4.17 (1H, m),5.33-5.49 (1H, m), 6.56 (1H, d, J=8.0 Hz), 6.80 (1H, d, J=8.3 Hz),6.98-7.15 (4H, m), 7.29-7.44 (4H, m), 7.68-7.78 (1H, m).

Example 204A2-Chloro-N-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)benzamideA) N-((4-Methylphenyl)sulfonyl)-N-phenyl-beta-alanine

A mixture of N-phenyl-beta-alanine (18.90 g), p-toluenesulfonyl chloride(21.80 g), pyridine (18.5 mL) and toluene (100 mL) was stirred at 100°C. for 15 hours. The reaction mixture was concentrated under reducedpressure, and water was added thereto, followed by extraction with ethylacetate. The extract was washed with water and saturated brine and driedover anhydrous magnesium sulfate, and then, the solvent was distilledoff under reduced pressure to obtain the title compound (30.80 g).

MS: [M+H]⁺ 319.9.

B) 2,3-Dihydroquinolin-4(1H)-one

To a solution of N-((4-methylphenyl)sulfonyl)-N-phenyl-beta-alanine(30.80 g) and DMF (0.5 mL) in THF (500 mL), oxalyl chloride (9.9 mL) wasadded at 0° C. The mixture was stirred at 0° C. for 1 hour. Then, thesolvent was distilled off under reduced pressure, and the mixture wasdried in a nitrogen atmosphere. The obtained solid was dissolved innitroethane (500 mL). To the solution, aluminum chloride (27.00 g) wasadded at 0° C. The reaction mixture was stirred at room temperature for2 hours, then poured to ice and basified with an aqueous sodiumhydroxide solution. Then, the insoluble matter was filtered off throughCelite. The obtained solution was subjected to extraction with ethylacetate. The extract was washed with water and saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. Acetic acid (30 mL) and concentratedhydrochloric acid (30 mL) were added to the obtained oil, and themixture was stirred under conditions of heating to reflux for 4 hours.The reaction was cooled to room temperature, then poured to ice andbasified with an aqueous sodium hydroxide solution. After extractionwith ethyl acetate, the extract was washed with water and saturatedbrine and then dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure to obtain the title compound(9.80 g).

MS: [M+H]⁺ 148.0.

C) 1-(3,4-Dimethoxybenzoyl)-2,3-dihydroquinolin-4(1H)-one

A mixture of 2,3-dihydroquinolin-4(1H)-one (2.70 g), ethylene glycol(2.1 mL), p-toluenesulfonic acid monohydrate (1.80 g), molecular sieves(4 Å, 3.00 g) and toluene (100 mL) was stirred under the conditions for3 hours. The reaction mixture was cooled to room temperature. Then,sodium bicarbonate was added thereto, and the mixture was diluted withwater, followed by extraction with ethyl acetate. The extract was washedwith water and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure.

To a solution of 3,4-dimethoxybenzoic acid (3.40 g) in THF (50 mL), acatalytic amount of DMF and oxalyl chloride (1.9 mL) were added at 0°C., and the mixture was stirred at room temperature for 30 minutes. Thesolvent was distilled off under reduced pressure, and then, the mixturewas dried in a nitrogen atmosphere. The obtained solid was dissolved inTHF (100 mL). To the solution, the oil obtained above and triethylamine(3.9 mL) were added, and the mixture was stirred at room temperature for2 hours. The reaction mixture was concentrated under reduced pressure,and water was added thereto, followed by extraction with ethyl acetate.The extract was washed with 6 N hydrochloric acid, and then, the solventwas distilled off under reduced pressure. THF and 6 N hydrochloric acidwere added to the residue, and the mixture was stirred at roomtemperature for 1 hour. The mixture was concentrated under reducedpressure again, and water was added thereto, followed by extraction withethyl acetate. The extract was washed with a saturated aqueous solutionof sodium bicarbonate and saturated brine and dried over anhydrousmagnesium sulfate, and then, the solvent was distilled off under reducedpressure. Toluene was added thereto, and the insoluble matter wasfiltered off. Then, the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (0.90g).

MS: [M+H]⁺ 311.9.

D)(3,4-Dimethoxyphenyl)(4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)methanone

To a solution of 1-(3,4-dimethoxybenzoyl)-2,3-dihydroquinolin-4(1H)-one(0.90 g) in THF (15 mL) and methanol (7 mL), sodium borohydride (0.11 g)was added at 0° C. After stirring at room temperature for 2 hours, waterwas added to the reaction mixture. The reaction mixture was concentratedunder reduced pressure, and water was added thereto, followed byextraction with ethyl acetate. The extract was washed with water andsaturated brine and dried over anhydrous magnesium sulfate, and then,the solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (0.62 g).

MS: [M+H]⁺ 314.0.

E) (4-Amino-3,4-dihydroquinolin-1(2H)-yl)(3,4-dimethoxyphenyl)methanonehydrochloride

To a solution of(3,4-dimethoxyphenyl)(4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)methanone(0.62 g) in toluene (10 mL), trifluoroborane diethyl ether complex (0.25mL) was added at 0° C., and then, trimethylsilylazide (0.29 mL) wasadded at the same temperature as above. The reaction mixture was stirredat room temperature for 1 hour and then stirred at 50° C. for 1 hour.The reaction was cooled to room temperature, and then, water was addedthereto, followed by extraction with ethyl acetate. The extract waswashed with water and saturated brine and dried over anhydrous magnesiumsulfate, and then, the solvent was distilled off under reduced pressure.A mixture of the residue, 10% palladium-carbon (containing 50% water,200 mg) and ethyl acetate (10 mL) was stirred at room temperature for 2hours in a hydrogen atmosphere. The insoluble matter was filtered off,and the solvent was distilled off under reduced pressure. Ethyl acetatewas added to the obtained residue, and then, a 4 M solution of hydrogenchloride in ethyl acetate (1 mL), then diethyl ether were added. Theobtained precipitate was collected by filtration to obtain the titlecompound (0.42 g).

MS: [M+H]⁺ 335.0 (M⁺+Na).

F)2-Chloro-N-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)benzamide

A mixture of(4-amino-3,4-dihydroquinolin-1(2H)-yl)(3,4-dimethoxyphenyl)methanonehydrochloride (0.20 g), 2-chlorobenzoyl chloride (0.075 mL),triethylamine (0.12 mL) and THF (15 mL) was stirred at 50° C. for 4hours and then diluted with water, followed by extraction with ethylacetate. The extract was washed with 1 N hydrochloric acid, a saturatedaqueous solution of sodium bicarbonate and saturated brine and driedover anhydrous magnesium sulfate. Then, the solvent was distilled offunder reduced pressure, and the residue was crystallized from ethylacetate/hexane to obtain the title compound (169 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.09-2.28 (1H, m), 2.33-2.53 (1H, m), 3.77(3H, s), 3.79-3.96 (1H, m), 3.88 (3H, s), 4.06-4.23 (1H, m), 5.38-5.54(1H, m), 6.59 (1H, d, J=8.1 Hz), 6.75 (1H, d, J=8.1 Hz), 6.89 (1H, dd,J=8.0, 1.2 Hz), 6.96-7.06 (3H, m), 7.06-7.12 (1H, m), 7.30-7.49 (4H, m),7.69-7.80 (1H, m).

Example 217A2-Chloro-N-(7-chloro-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl)benzamideA) N-(6-Chloropyridin-2-yl)-beta-alanine

A mixture of 2-amino-6-chloropyridine (100 g), methyl acrylate methylacrylate (117 g) and acetic acid (34 mL) was stirred at 120° C. for 72hours. The reaction was cooled to room temperature. Then, a 6 N aqueoussodium hydroxide solution (375 mL) was added thereto, and the mixturewas stirred under conditions of heating to reflux for 5 hours. Thereaction mixture was cooled to room temperature, and then, unreacted2-amino-6-chloropyridine starting material was extracted with diethylether. The remaining aqueous layer was adjusted to pH=4 to 5 with 3 Nhydrochloric acid, and the precipitate was collected by filtration. Thesolid collected by filtration was dissolved in ethyl acetate, washedwith saturated brine and dried over anhydrous sodium sulfate. Then, thesolvent was distilled off under reduced pressure to obtain the titlecompound (60 g).

¹HNMR (300 MHz, MeOD) δ 2.58 (2H, t, J=6.8 Hz), 3.54 (2H, t, J=6.8 Hz),6.38 (1H, dd, J=8.4, 0.6 Hz), 6.49 (1H, dd, J=7.2, 0.6 Hz), 7.33 (1H,dd, J=8.4, 7.4 Hz).

B) 7-Chloro-2,3-dihydro-1,8-naphthyridin-4(1H)-one

A mixture of N-(6-chloropyridin-2-yl)-beta-alanine (40 g) and Eaton'sReagent (600 mL) was stirred at 75° C. for 3 hours. The reaction mixturewas poured to ice water and basified to pH=10 with sodium hydroxide,followed by extraction with ethyl acetate. The extract was washed withsaturated brine and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (ethyl acetate) to obtain the titlecompound.

MS: [M+H]⁺ 182.8.

C)7-Chloro-1-(3,4-dimethoxybenzoyl)-2,3-dihydro-1,8-naphthyridin-4(1H)-onetrifluoroacetic Acid Salt

To a solution of 7-chloro-2,3-dihydro-1,8-naphthyridin-4(1H)-one (0.6 g)in THF (30 mL), a 1 M solution of lithium bis(trimethylsilyl)amide inhexane (3.3 mL) was added at −75° C. to −70° C. The reaction mixture wasstirred at the same temperature as above for 30 minutes, and then, asolution of 3,4-dimethoxybenzoyl chloride (0.8 g) in THF (5 mL) wasadded thereto over 30 minutes. The temperature of the reaction mixturewas raised to room temperature, and the reaction mixture was poured towater, followed by extraction with ethyl acetate. The extract was washedwith saturated brine and dried over anhydrous sodium sulfate, and then,the solvent was distilled off under reduced pressure. The residue waspurified by reverse-phase HPLC to obtain the title compound (28 mg).

MS: [M+H]⁺ 346.9.

D)(4-Amino-7-chloro-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)(3,4-dimethoxyphenyl)methanone

A mixture of7-chloro-1-(3,4-dimethoxybenzoyl)-2,3-dihydro-1,8-naphthyridin-4(1H)-onetrifluoroacetic acid salt (28 mg), hydroxylamine hydrochloride (15 mg)and pyridine (5 mL) was stirred under conditions of heating to refluxfor 4 hours. The reaction mixture was concentrated under reducedpressure, and water was added thereto, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and then, the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate). To a solution of the obtained residueand molybdenum trioxide (14 mg) in THF (2 mL) and methanol (2 mL),sodium borohydride (12 mg) was added, and the mixture was stirred atroom temperature for 14 hours. Water was added to the reaction, and themixture was concentrated under reduced pressure. Water was addedthereto, followed by extraction with ethyl acetate. The extract waswashed with saturated brine and dried over anhydrous magnesium sulfate,and then, the solvent was distilled off under reduced pressure to obtainthe title compound (24 mg).

MS: [M+H]⁺ 348.0.

E)2-Chloro-N-(7-chloro-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl)benzamide

A mixture of(4-amino-7-chloro-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)(3,4-dimethoxyphenyl)methanone(24 mg), 2-chlorobenzoyl chloride (0.012 mL), triethylamine (0.020 mL)and THF (5 mL) was stirred at room temperature for 64 hours. Thereaction mixture was concentrated under reduced pressure, and water wasadded thereto, followed by extraction with ethyl acetate. The extractwas washed with a saturated aqueous solution of sodium bicarbonate andsaturated brine and dried over anhydrous magnesium sulfate, and then,the solvent was distilled off under reduced pressure to obtain the titlecompound (12 mg).

¹H NMR (300 MHz, CDCl₃) δ 2.19-2.33 (1H, m), 2.39-2.51 (1H, m), 3.84(3H, s), 3.89 (3H, s), 3.91-4.03 (1H, m), 4.06-4.25 (1H, m), 5.38-5.59(1H, m), 6.46-6.62 (1H, m), 6.73 (1H, d, J=8.3 Hz), 6.85-6.93 (1H, m),6.93-7.00 (1H, m), 7.12 (1H, d, J=1.9 Hz), 7.31-7.46 (3H, m), 7.66-7.82(2H, m).

Example 4B2-Chloro-N-(trans-1-(3,4-dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamideA) tert-Butyltrans-4-(((benzyloxy)carbonyl)amino)-3-phenylpiperidine-1-carboxylate

To a solution oftrans-1-(tert-butoxycarbonyl)-3-phenylpiperidine-4-carboxylic acid (1.0g) in toluene (25 mL), diphenyl phosphorazidate (0.77 mL) andtriethylamine (0.50 mL) were added at room temperature, and the mixturewas heated to reflux for 1 hour. Benzyl alcohol (0.41 mL) was added tothe reaction mixture at room temperature, and the mixture was heated toreflux for 5 hours. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The organic layer was washed with waterand saturated brine and then dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (1.35 g).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 2.10-2.27 (1H, m), 2.46-2.64(1H, m), 2.67-2.98 (2H, m), 3.83-4.03 (1H, m), 4.11-4.30 (2H, m), 4.47(1H, brs), 4.70 (1H, d, J=5.8 Hz), 4.95 (2H, s), 7.09-7.49 (10H, m).

B) tert-Butyl trans-4-amino-3-phenylpiperidine-1-carboxylate

A mixture of tert-butyltrans-4-(((benzyloxy)carbonyl)amino)-3-phenylpiperidine-1-carboxylate(1.3 g), 10% palladium-carbon (200 mg) and methanol (30 mL) was stirredovernight at room temperature in a hydrogen atmosphere. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure to obtain the title compound (863.5 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 1.74 (3H, brs), 1.83-2.04 (1H,m), 2.39 (1H, td, J=11.0, 4.1 Hz), 2.66-2.93 (2H, m), 3.01 (1H, td,J=10.7, 3.9 Hz), 3.99-4.35 (2H, m), 7.03-7.42 (5H, m).

C) tert-Butyltrans-4-((2-chlorobenzoyl)amino)-3-phenylpiperidine-1-carboxylate

To a mixture of tert-butyltrans-4-amino-3-phenylpiperidine-1-carboxylate (484 mg), triethylamine(0.15 mL) and THF (10 mL), 2-chlorobenzoyl chloride (0.11 mL) was addedat 0° C. After stirring overnight at room temperature, water was addedto the reaction mixture, followed by extraction with ethyl acetate. Theorganic layer was washed with 1 N hydrochloric acid, a saturated aqueoussolution of sodium carbonate and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound(247.6 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.47 (9H, s), 2.26-2.45 (1H, m), 2.61-2.76(1H, m), 2.76-2.90 (1H, m), 2.90-3.06 (1H, m), 4.17-4.38 (2H, m),4.38-4.59 (1H, m), 5.84 (1H, d, J=8.3 Hz), 7.11-7.40 (10H, m).

D)2-Chloro-N-(trans-1-(3,4-dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

To tert-butyltrans-4-((2-chlorobenzoyl)amino)-3-phenylpiperidine-1-carboxylate (240mg), a 4 M solution of hydrogen chloride in ethyl acetate (10 mL) wasadded under ice cooling, and the mixture was stirred at room temperaturefor 2 hours. The reaction mixture was concentrated under reducedpressure, and the obtained residue was dissolved in pyridine (5 mL). Tothe solution, 3,4-dimethoxybenzoyl chloride (117 mg) was added at 0° C.The reaction mixture was stirred overnight at room temperature, andthen, the solvent was distilled off under reduced pressure. The residuewas partitioned into 1 N hydrochloric acid and ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumcarbonate and saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (217.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.37-1.68 (1H, m), 1.82-2.17 (1H, m),2.70-2.90 (1H, m), 2.90-3.30 (2H, m), 3.78 (6H, s), 3.61-4.06 (1H, m),4.42 (2H, d, J=10.9 Hz), 6.88 (1H, d, J=6.8 Hz), 6.92-7.05 (3H, m),7.10-7.49 (8H, m), 8.27 (1H, d, J=8.9 Hz).

Example 23BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-5-carboxamideA) Methyl 8-chloroquinoxaline-6-carboxylate

A mixture of methyl 3,4-diamino-5-chlorobenzoate (2.80 g), a 40% aqueousoxalaldehyde solution (2.43 g), methanol (20 mL) and THF (10 mL) wasstirred overnight at room temperature. The reaction mixture was dilutedwith a saturated aqueous solution of sodium bicarbonate, followed byextraction with THF/ethyl acetate. The extract was washed with saturatedbrine and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was washed with ethylacetate to obtain the title compound (1.28 g).

MS: [M+H]⁺ 222.8.

B) 8-Chloroquinoxaline-6-carboxylic acid

A mixture of methyl 8-chloroquinoxaline-6-carboxylate (1.27 g), a 8 Maqueous sodium hydroxide solution (7.13 mL), methanol (2 mL) and THF (10mL) was stirred at 50° C. for 10 hours. The reaction mixture wasconcentrated under reduced pressure, and the residue was washed withwater and diisopropyl ether to obtain the title compound (1.11 g).

MS: [M+H]⁺ 209.0.

C) (3S,4R)-tert-Butyl3-phenyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate

To a solution of (3S,4R)-tert-butyl4-amino-3-phenylpiperidine-1-carboxylate (2.50 g) and triethylamine (2.5mL) in THF (50 mL), trifluoroacetic anhydride (1.4 mL) was added underice cooling, and the mixture was stirred at room temperature for 2hours. The reaction mixture was diluted with a saturated aqueoussolution of sodium bicarbonate, followed by extraction with ethylacetate. The extract was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (2.80g).

¹H NMR (300 MHz, CDCl₃) δ 1.46 (9H, s), 1.81 (2H, d, J=4.9 Hz),3.09-3.19 (1H, m), 3.19-3.69 (2H, m), 3.56-4.14 (2H, m), 4.31-4.45 (1H,m), 5.91 (1H, brs), 7.18-7.25 (2H, m), 7.29-7.38 (3H, m).

D) 2,2,2-Trifluoro-N-((3S,4R)-3-phenylpiperidin-4-yl)acetamidehydrochloride

To a solution of (3S,4R)-tert-butyl3-phenyl-4-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate (2.77 g)in methanol (5 mL), a 4 M solution of hydrochloric acid in cyclopentylmethyl ether (9.5 mL) was added, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure, and the residue was washed with diisopropyl ether toobtain the title compound (2.01 g).

MS: [M+H]⁺ 273.0.

E)N-((3S,4R)-1-(8-Chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-2,2,2-trifluoroacetamide

A mixture of 2,2,2-trifluoro-N-((3S,4R)-3-phenylpiperidin-4-yl)acetamidehydrochloride (1.40 g), 8-chloroquinoxaline-6-carboxylic acid (1.23 g),HATU (2.24 g), triethylamine (2.0 mL) and DMF (10 mL) was stirred atroom temperature for 3 hours. The reaction mixture was diluted with asaturated aqueous solution of sodium bicarbonate, followed by extractionwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (1.99 g).

MS: [M+H]⁺ 463.1.

F)((3S,4R)-4-Amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone

To a solution ofN-((3S,4R)-1-(8-chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-2,2,2-trifluoroacetamide(1.98 g) in methanol (10 mL), a 2 M aqueous sodium hydroxide solution(9.5 mL) was added at room temperature, and the mixture was stirred atthe same temperature as above for 2 hours. The reaction mixture wasneutralized with 1 M hydrochloric acid, followed by extraction withethyl acetate. The extract was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(1.32 g).

MS: [M+H]⁺ 367.0.

G)N-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

A mixture of((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(200 mg), 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (92 mg), HATU (249mg), triethylamine (0.228 mL) and DMF (2 mL) was stirred at roomtemperature for 2 hours. Then, the reaction mixture was diluted with asaturated aqueous solution of sodium bicarbonate, followed by extractionwith ethyl acetate. The extract was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (NH, ethyl acetate/hexane) and then crystallizedfrom ethyl acetate/diisopropyl ether to obtain the title compound (209mg).

¹H NMR (300 MHz, CDCl₃) δ 1.74-2.15 (2H, m), 2.20 (3H, s), 3.11-3.48(1H, m), 3.51-3.97 (2H, m), 4.02 (3H, s), 4.20-4.69 (2H, m), 5.48-5.79(1H, m), 5.89 (1H, brs), 7.06-7.52 (6H, m), 7.63-8.25 (2H, m), 8.98 (2H,brs).

Example 24BN-((3S,4R)-1-(8-Chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-6-(2-morpholinoethoxy)nicotinamideA)6-Chloro-N-((3S,4R)-1-(8-chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)nicotinamide

To a solution of((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(200 mg), 6-chloronicotinic acid (103 mg) and triethylamine (0.227 ml)in DMF (2 ml), HATU (249 mg) was added at room temperature. Afterstirring at room temperature for 1 hour in a dry atmosphere, a saturatedaqueous solution of sodium bicarbonate was added thereto, followed byextraction with ethyl acetate. The extract was washed with water andsaturated brine and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane). Theobtained solid was washed with diisopropyl ether to obtain the titlecompound (273 mg).

MS: [M+H]⁺ 506.1

B)N-((3S,4R)-1-(8-Chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-6-(2-morpholinoethoxy)nicotinamide

To a solution of N-(2-hydroxyethyl)morpholine (0.072 ml) in THF (1.3ml), sodium hydride (60%, 24.17 mg) was added at 0° C. After stirring at0° C. for 20 minutes,6-chloro-N-((3S,4R)-1-(8-chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)nicotinamide(60 mg) was added thereto, and the mixture was stirred at 70° C. for 1.5hours. A saturated aqueous solution of ammonium chloride was added tothe reaction mixture at room temperature, followed by extraction withethyl acetate. The extract was washed with water and saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff. The residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (18.40 mg).

¹H NMR (300 MHz, DMSO) δ 1.65-2.09 (2H, m), 2.34-2.47 (5H, m), 2.62-2.72(2H, m), 3.50-3.68 (6H, m), 3.99-4.50 (4H, m, J=5.5, 5.5 Hz), 4.52-4.76(1H, m), 6.84 (1H, d, J=8.7 Hz), 7.07-7.41 (5H, m), 7.87-8.29 (4H, m),8.36-8.50 (1H, m), 9.01-9.20 (2H, m, J=19.6 Hz).

Example 31BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(difluoromethoxy)pyridine-2-carboxamide

To a solution of 3-(difluoromethoxy)picolinic acid (70.5 mg),((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(97.2 mg) and N-ethyldiisopropylamine (0.139 mL) in DMF (2.0 mL), HATU(161 mg) was added at room temperature, and the mixture was stirred for3 hours. Water was added to the reaction mixture, followed by extractionwith ethyl acetate/THF. The extract was washed with a saturated aqueoussolution of potassium carbonate, water and saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (NH, ethyl acetate/hexane) to obtain the titlecompound (121 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.61-2.15 (2H, m), 3.34-3.47 (1H, m),3.48-3.74 (2H, m), 3.78-3.99 (1H, m), 4.09-4.49 (1H, m), 4.52-4.69 (1H,m), 6.72-7.45 (6H, m), 7.57 (1H, dd, J=8.4, 4.6 Hz), 7.72 (1H, d, J=7.7Hz), 8.02 (1H, d, J=11.1 Hz), 8.13 (1H, brs), 8.45 (1H, d, J=3.8 Hz),8.55-8.74 (1H, m), 8.97-9.20 (2H, m).

Example 42BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-oxo-1,6-dihydropyridine-2-carboxamideA)N-((3S,4R)-1-(8-Chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-6-methoxypicolinamide

To a solution of 6-methoxypicolinic acid (0.052 g),((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(0.083 g) and N-ethyldiisopropylamine (0.12 mL) in DMF (2.0 mL), HATU(0.13 g) was added at room temperature, and the mixture was stirred for16 hours. Water was added to the reaction mixture, followed byextraction with ethyl acetate/THF. The extract was washed with asaturated aqueous solution of potassium carbonate, water and saturatedbrine and then dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to obtain thetitle compound (0.11 g).

MS: [M+H]⁺ 502.1.

B)N-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

In a nitrogen atmosphere, pyridinium chloride (0.18 g) was added to amixture ofN-((3S,4R)-1-(8-chloroquinoxaline-6-carbonyl)-3-phenylpiperidin-4-yl)-6-methoxypicolinamide(0.077 g) and DMF (0.2 mL) at room temperature, and the resultingmixture was stirred at 130° C. for 16 hours. To the reaction mixture, 1M hydrochloric acid was added at room temperature, and the deposit wascollected by filtration and washed with water. The obtained solid wasdissolved in THF, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(methanol/ethyl acetate) to obtain the title compound (0.019 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-2.14 (2H, m), 3.35-4.45 (6H, m),4.47-4.61 (1H, m), 6.60-6.79 (1H, m), 6.94-7.43 (6H, m), 7.58-7.73 (1H,m), 7.94-8.49 (3H, m), 9.01-9.25 (2H, m).

Example 45BN-((3S,4R)-1-((8-Methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamideA) tert-Butyl(3S,4R)-3-phenyl-4-(((3-(trifluoromethyl)pyridin-2-yl)carbonyl)amino)piperidine-1-carboxylate

To a solution of 3-(trifluoromethyl)picolinic acid (2.57 g), tert-butyl(3S,4R)-4-amino-3-phenylpiperidine-1-carboxylate (3.1 g) and HOBt (2.27g) in DMF (40 mL), WSC (2.95 mL) was added under ice cooling, and themixture was stirred overnight at room temperature. The solvent wasdistilled off under reduced pressure, and water was added to theresidue, followed by extraction with ethyl acetate. The extract waswashed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (5.02 g).

MS: [M+H−Boc]⁺350.2.

B)N-((3S,4R)-3-Phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamidehydrochloride

To tert-butyl(3S,4R)-3-phenyl-4-(((3-(trifluoromethyl)pyridin-2-yl)carbonyl)amino)piperidine-1-carboxylate(4.29 g), a 4 M solution of hydrogen chloride in ethyl acetate (50 mL)was added under ice cooling, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distilled off under reducedpressure to obtain the title compound (4.29 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.89 (1H, d, J=13.4 Hz), 2.10-2.32 (1H, m),2.92-3.15 (1H, m), 3.19-3.36 (2H, m), 3.39-3.55 (1H, m), 3.74 (1H, q,J=11.4 Hz), 4.62 (1H, d, J=6.2 Hz), 7.16-7.38 (5H, m), 7.69 (1H, dd,J=7.8, 4.8 Hz), 8.24 (1H, d, J=7.5 Hz), 8.83 (1H, d, J=4.3 Hz), 8.94(1H, d, J=9.2 Hz), 9.27 (1H, d, J=9.2 Hz), 9.77 (1H, d, J=9.0 Hz).

C) 2-Methoxy-6-nitroaniline

To a solution of 2-amino-3-nitrophenol (9.12 g) and potassium carbonate(13.6 g) in DMF (100 mL), iodomethane (4.44 mL) was added at roomtemperature, and the mixture was stirred at room temperature for 2hours. Water was added to the reaction mixture at room temperature. Thedeposited solid was collected by filtration and washed with water andhexane to obtain the title compound (9.85 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (3H, s), 6.61 (1H, dd, J=8.9, 7.7 Hz),6.95-7.17 (3H, m), 7.59 (1H, dd, J=8.9, 1.3 Hz).

D) 4-Bromo-2-methoxy-6-nitroaniline

To a solution of 2-methoxy-6-nitroaniline (9.12 g) in acetonitrile (100mL), N-bromosuccinimide (10.8 g) was added at room temperature, and themixture was stirred at 70° C. for 4 hours. An aqueous sodium thiosulfatesolution was added to the reaction mixture at room temperature. Thedeposited solid was collected by filtration and washed with water andhexane to obtain the title compound (11.77 g).

¹H NMR (300 MHz, DMSO-d₆) δ 3.91 (3H, s), 7.20 (1H, d, J=2.1 Hz), 7.25(2H, brs), 7.72 (1H, d, J=2.1 Hz).

E) N-(4-Bromo-2-methoxy-6-nitrophenyl)acetamide

To a solution of 4-bromo-2-methoxy-6-nitroaniline (11.8 g) and aceticanhydride (6.74 mL) in acetic acid (40 mL), concentrated sulfuric acid(2.54 mL) was added at room temperature, and the mixture was stirred at70° C. for 2 hours. Water was added to the reaction mixture at roomtemperature, and the deposited solid was collected by filtration andwashed with water. The solid was dried by azeotroping with toluene, andsuspended in ethyl acetate. The solid was collected by filtration andwashed with ethyl acetate and diisopropyl ether to obtain the titlecompound (9.55 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.01 (3H, s), 3.93 (3H, s), 7.62 (1H, d,J=2.1 Hz), 7.66 (1H, d, J=2.1 Hz), 9.91 (1H, s).

F) N-(4-Cyano-2-methoxy-6-nitrophenyl)acetamide

A solution of N-(4-bromo-2-methoxy-6-nitrophenyl)acetamide (2.04 g),zinc dicyanide (1.76 g) and tetrakis(triphenylphosphine)palladium (857mg) in DMF (20 mL) was stirred at 170° C. for 1 hour under irradiationwith microwave. The reaction mixture was neutralized by the addition ofan aqueous potassium carbonate solution, followed by extraction withethyl acetate and THF. The extract was washed with water and saturatedbrine and then dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The residue was washed withethyl acetate and diisopropyl ether to obtain the title compound (967mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.07 (3H, s), 3.97 (3H, s), 7.90 (1H, d,J=1.7 Hz), 8.02 (1H, d, J=1.7 Hz), 10.29 (1H, s).

G) Methyl 4-amino-3-methoxy-5-nitrobenzoate

To a solution of N-(4-cyano-2-methoxy-6-nitrophenyl)acetamide (967 mg)in ethanol (10 mL), a 8 M aqueous sodium hydroxide solution (5.14 mL)was added at room temperature, and the mixture was heated to reflux for3 hours. To the reaction mixture, 2 M hydrochloric acid (20.6 mL) wasadded at 0° C., and the deposited solid was collected by filtration. Toa solution of the obtained solid and potassium carbonate (1.11 g) in DMF(15 mL), iodomethane (0.39 mL) was added at room temperature, and themixture was stirred at room temperature for 2 hours. Water was added tothe reaction mixture, and the deposited solid was collected byfiltration and washed with water and hexane to obtain the title compound(579 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.84 (3H, s), 3.94 (3H, s), 7.41 (1H, d,J=1.7 Hz), 7.67 (2H, brs), 8.27 (1H, d, J=1.7 Hz).

H) Methyl 3,4-diamino-5-methoxybenzoate

A mixture of methyl 4-amino-3-methoxy-5-nitrobenzoate (579 mg), 10%palladium-carbon (347 mg), methanol (20 mL) and THF (10 mL) was stirredovernight at room temperature in a hydrogen atmosphere. The insolublematter was filtered off, and the filtrate was concentrated under reducedpressure to obtain the title compound (522.8 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.73 (3H, s), 3.76 (3H, s), 4.74 (2H, s),4.81 (2H, s), 6.83 (1H, d, J=1.7 Hz), 6.97 (1H, d, J=1.7 Hz).

I) Methyl 8-methoxyquinoxaline-6-carboxylate

To a solution of methyl 3,4-diamino-5-methoxybenzoate (528 mg) inmethanol (5 mL) and THF (10 mL), a 40% aqueous oxalaldehyde solution(0.46 mL) was added at room temperature, and the mixture was stirred atroom temperature for 2 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The extract was washed withwater and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (249 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 3.96 (3H, s), 4.08 (3H, s), 7.66 (1H, d,J=1.5 Hz), 8.22 (1H, d, J=1.5 Hz), 9.01 (1H, d, J=1.7 Hz), 9.06 (1H, d,J=1.7 Hz).

J) 8-Methoxyquinoxaline-6-carboxylic acid

To a solution of methyl 8-methoxyquinoxaline-6-carboxylate (249 mg) inmethanol (2 mL) and THF (4 mL), a 1 M aqueous sodium hydroxide solution(5.14 mL) was added at room temperature, and the mixture was stirred atroom temperature for 2 hours. To the reaction mixture, 1 M hydrochloricacid was added at room temperature, and the deposited solid wascollected by filtration and washed with water and diisopropyl ether toobtain the title compound (160.4 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 4.07 (3H, s), 7.67 (1H, d, J=1.5 Hz), 8.20(1H, d, J=1.7 Hz), 8.99 (1H, d, J=1.7 Hz), 9.04 (1H, d, J=1.7 Hz), 13.53(1H, brs).

K)N-((3S,4R)-1-((8-Methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-((3S,4R)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamidehydrochloride (100 mg), 8-methoxyquinoxaline-6-carboxylic acid (62 mg),HOBt (61 mg) and triethylamine (0.11 mL) in DMF (1 mL), WSC (0.07 mL)was added at room temperature, and the mixture was stirred at roomtemperature for 16 hours. An aqueous potassium carbonate solution wasadded to the reaction mixture at room temperature, followed byextraction with ethyl acetate. The extract was washed with water andsaturated brine and then dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, methanol/ethylacetate) to obtain the title compound (79.6 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.62-2.12 (2H, m), 3.28-3.90 (4H, m),3.91-4.11 (3H, m), 4.17-4.54 (1H, m), 4.55-4.71 (1H, m), 7.09-7.47 (6H,m), 7.50-7.77 (2H, m), 8.24 (1H, d, J=8.1 Hz), 8.69-9.11 (4H, m).

Example 47BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2-hydroxyethoxy)-4-(trifluoromethyl)nicotinamideA)N-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-4-(trifluoromethyl)nicotinamide

To a solution of 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (0.59 mL) in THF(10 mL), sodium hydride (60%, 178 mg) was added at 0° C., and themixture was stirred at 0° C. for 3 hours.6-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-4-(trifluoromethyl)nicotinamide(500 mg) was added to the reaction mixture, and the mixture was stirredovernight at room temperature. A saturated aqueous solution of ammoniumchloride was added to the reaction mixture at room temperature, followedby extraction with ethyl acetate. The extract was washed with water andsaturated brine and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, methanol/ethylacetate) to obtain the title compound (313 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.43-1.59 (3H, m), 1.66-1.91 (2H, m),2.05-2.29 (2H, m), 3.24-3.57 (2H, m), 3.57-4.08 (6H, m), 4.30-4.81 (5H,m), 5.66 (1H, brs), 7.02 (1H, s), 7.14-7.49 (6H, m), 7.60-8.23 (3H, m),8.97 (2H, brs).

B)N-((3S,4R)-1-((8-Methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamide

ToN-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-4-(trifluoromethyl)nicotinamide(300 mg), a 4 M solution of hydrogen chloride in ethyl acetate (20 mL)was added, and the mixture was stirred at room temperature for 3 hours.The reaction mixture was concentrated under reduced pressure, and theobtained residue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (161.3 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.51-1.96 (1H, m), 1.98-2.15 (1H, m),3.35-4.02 (6H, m), 4.21-4.53 (3H, m), 4.59 (1H, brs), 4.86 (1H, t, J=5.5Hz), 6.90-7.48 (6H, m), 7.86 (1H, d, J=10.5 Hz), 7.96-8.21 (2H, m), 8.72(1H, d, J=8.3 Hz), 9.10 (2H, d, J=19.4 Hz).

Example 48B Dibenzyl2-((5-(((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)carbamoyl)-4-(trifluoromethyl)pyridin-2-yl)oxy)ethylphosphate

To a mixture ofN-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2-hydroxyethoxy)-4-(trifluoromethyl)nicotinamide(120 mg), tetrabenzyl diphosphate (151 mg) and THF (5 mL), a 1.9 Msolution of sodium bis(trimethylsilyl)amide in THF (0.26 mL) was addedat 0° C. After stirring at 0° C. for 2 hours, a saturated aqueoussolution of sodium carbonate was added to the reaction mixture at 0° C.,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and then dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (47.9 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.79 (2H, brs), 2.13 (2H, brs), 3.31 (1H,brs), 3.67 (2H, brs), 3.84-4.01 (1H, m), 4.20-4.32 (2H, m), 4.37-4.57(3H, m), 4.73 (1H, brs), 4.83-5.12 (4H, m), 6.15 (1H, brs), 6.86 (1H,s), 7.05-7.42 (13H, m), 7.51-8.22 (3H, m), 8.96 (2H, brs).

Example 55BN-(cis-1′-(3,4-Dimethoxybenzoyl)-1,3′-bipiperidin-4′-yl)-2-(trifluoromethoxy)benzamideA) (cis-4-Azido-3-hydroxypiperidin-1-yl)(3,4-dimethoxyphenyl)methanone

To a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (5.1g) in toluene (50 mL), 70% m-CPBA (7.4 g) was added at room temperature,and the mixture was stirred at room temperature for 16 hours. Thedeposit was filtered off, and the solvent in the filtrate was distilledoff under reduced pressure. An aqueous sodium thiosulfate solution wasadded to the residue, followed by extraction with ethyl acetate. Theextract was washed with a saturated aqueous solution of sodiumbicarbonate and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure toobtain tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (6.8g).

To a solution of tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (8.1 g) in DMF (80 mL),THF (60 mL) and water (20 mL), sodium azide (8.0 g) was added at roomtemperature, and the mixture was stirred at 90° C. for 3 hours in anitrogen atmosphere. Water was added to the reaction mixture at roomtemperature, followed by extraction with ethyl acetate. The extract waswashed with water and saturated brine and then dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. A 4 M solution of hydrogen chloride in ethyl acetate (50 mL)was added to the obtained residue at room temperature, and the mixturewas stirred at room temperature for 20 minutes. The solvent wasdistilled off under reduced pressure. To a solution of the obtainedresidue, 3,4-dimethoxybenzoic acid (7.5 g), HOBt (8.1 g) andtriethylamine (28 mL) in DMF (80 mL), WSC (7.1 mL) was added at roomtemperature, and the mixture was stirred for 16 hours. Water was addedto the reaction mixture, followed by extraction with ethyl acetate/THF.The extract was washed with a saturated aqueous solution of potassiumcarbonate, water and saturated brine and then dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(NH, ethyl acetate/hexane) to obtain the title compound (3.6 g).

MS: [M+H]⁺ 307.0.

B)(cis-4-Azido-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)(3,4-dimethoxyphenyl)methanone

To a solution of(cis-4-azido-3-hydroxypiperidin-1l-yl)(3,4-dimethoxyphenyl)methanone(1.0 g) and imidazole (1.24 g) in DMF (10 mL), TBSCl (1.6 g) was addedat room temperature, and the mixture was stirred for 2 hours. Water wasadded to the reaction mixture, followed by extraction with ethylacetate. The extract was washed with water and saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane) to obtain the titlecompound (1.3 g).

MS: [M+H]⁺ 421.2.

C) tert-Butyl(cis-3-((tert-butyldimethylsilyl)oxy)-1-(3,4-dimethoxybenzoyl)piperidin-4-yl)carbamate

A mixture of(cis-4-azido-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)(3,4-dimethoxyphenyl)methanone(1.3 g), 10% palladium-carbon (0.76 g) and THF (20 mL) was stirred atroom temperature for 16 hours in a hydrogen atmosphere (1 atm). Thereaction mixture was filtered, and the solvent in the filtrate wasdistilled off under reduced pressure.

To a solution of the obtained residue and triethylamine (1.3 mL) in THF(20 mL), di-tert-butyl dicarbonate (0.84 mL) was added at roomtemperature, and the mixture was stirred for 10 minutes. Water was addedto the reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(1.3 g).

MS: [M+H]⁺ 495.3.

D) tert-Butyl(cis-1-(3,4-dimethoxybenzoyl)-3-hydroxypiperidin-4-yl)carbamate

To a solution of tert-butyl(cis-3-((tert-butyldimethylsilyl)oxy)-1-(3,4-dimethoxybenzoyl)piperidin-4-yl)carbamate(1.3 g) in THF (20 mL), a 1.0 M solution of TBAF in THF (7.5 mL) wasadded at room temperature, and the mixture was stirred for 10 minutes.Water was added to the reaction mixture, followed by extraction withethyl acetate. The extract was washed with water and saturated brine andthen dried over anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (NH, methanol/ethyl acetate) to obtain thetitle compound (0.83 g).

MS: [M+H]⁺ 381.2.

E)N-(cis-3-Azido-1-(3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy)benzamide

To a solution of tert-butyl(cis-1-(3,4-dimethoxybenzoyl)-3-hydroxypiperidin-4-yl)carbamate (0.40 g)and triethylamine (0.44 mL) in THF (5 mL), methanesulfonyl chloride(0.12 mL) was added under ice cooling, and the mixture was stirred for10 minutes. Water was added to the reaction mixture, followed byextraction with ethyl acetate. The extract was washed with water andsaturated brine and then dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure. To a solution of theresidue in DMF (5 mL), sodium azide (0.16 g) and sodium acetate (0.18 g)were added at room temperature, and the mixture was stirred at 80° C.for 30 minutes, at 100° C. for 30 minutes and at 120° C. for 1 hour in anitrogen atmosphere. Water was added to the reaction mixture at roomtemperature, followed by extraction with ethyl acetate. The extract waswashed with water and saturated brine and then dried over anhydrousmagnesium sulfate, and the solvent was distilled off under reducedpressure. A 4 M solution of hydrogen chloride in ethyl acetate (5.0 mL)was added to the obtained residue at room temperature, and the mixturewas stirred at room temperature for 10 minutes. The solvent wasdistilled off under reduced pressure. To a solution of the residue inDMF (5.0 mL), 2-(trifluoromethoxy)benzoic acid (0.32 g), HOBtmonohydrate (0.25 g), triethylamine (0.74 mL) and WSC (0.37 mL) wereadded at room temperature, and the mixture was stirred at roomtemperature for 16 hours. Water was added to the reaction mixture,followed by extraction with ethyl acetate. The extract was washed withwater and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to obtain the title compound (0.092 g).

MS: [M+H]⁺ 494.1.

F)N-(cis-1′-(3,4-Dimethoxybenzoyl)-1,3′-bipiperidin-4′-yl)-2-(trifluoromethoxy)benzamide

A mixture ofN-(cis-3-azido-1-(3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy)benzamide(0.092 g), 10% palladium-carbon (0.092 g) and methanol (5.0 mL) wasstirred at room temperature for 1 hour in a hydrogen atmosphere (1 atm).The reaction mixture was filtered, and the solvent in the filtrate wasdistilled off under reduced pressure. To a mixture of the obtainedresidue, glutaraldehyde (0.20 mL), DMF (3.0 mL) and acetic acid (1.0mL), sodium triacetoxyborohydride (0.25 g) was added at roomtemperature, and the resulting mixture was stirred at room temperaturefor 30 minutes. An aqueous potassium carbonate solution was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas back-extracted with 2 N hydrochloric acid and basified with anaqueous potassium carbonate solution, followed by extraction with ethylacetate. The extract was washed with water and saturated brine and thendried over anhydrous magnesium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (NH, ethyl acetate/hexane) to obtain the titlecompound (0.020 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.22-1.59 (7H, m), 1.60-1.87 (2H, m),2.28-2.50 (6H, m), 3.08-3.28 (1H, m), 3.35-3.70 (1H, m), 3.78 (3H, s),3.79 (3H, s), 4.45-4.66 (1H, m), 6.89-7.04 (3H, m), 7.40-7.64 (4H, m),8.46 (1H, d, J=8.1 Hz).

Example 59B5-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamideA) (3S,4R)-tert-Butyl4-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamide)-3-(4-fluorophenyl)piperidine-1-carboxylate

A solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (148mg), HATU (420 mg) and N-ethyldiisopropylamine (0.3 mL) in DMF (3 mL)was stirred at room temperature for 15 minutes.5-Chloro-N-((3S,4R)-3-(4-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide(250 mg) was added to the reaction mixture at room temperature, and themixture was stirred at room temperature for 16 hours. Water was added tothe reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (210mg).

MS: [M+H−100]⁺450.9.

B)5-Chloro-N-((3S,4R)-3-(4-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

To a solution of (3S,4R)-tert-butyl4-(5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxamide)-3-(4-fluorophenyl)piperidine-1-carboxylate(0.73 g) in dichloromethane (4 mL), TFA (1 mL) was added at roomtemperature, and the mixture was stirred at room temperature for 2hours. The solvent was distilled off under reduced pressure. A saturatedaqueous solution of sodium bicarbonate was added to the residue,followed by extraction with ethyl acetate. The extract was washed withwater and saturated brine and then dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure to obtain acrude product of the title compound. This compound was used in the nextstep without purification.

MS: [M+H]⁺ 350.9.

C)5-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

A solution of 8-chloroquinoxaline-6-carboxylic acid (65.4 mg), HATU (163mg) and N-ethyldiisopropylamine (0.13 mL) in DMF (2 mL) was stirred atroom temperature for 15 minutes.5-Chloro-N-((3S,4R)-3-(4-fluorophenyl)piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide(100 mg) was added to the reaction mixture at room temperature, and themixture was stirred at room temperature for 16 hours. Water was added tothe reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (110mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.70-2.21 (5H, m), 3.39-3.41 (1H, m),3.50-3.68 (5H, m), 3.79-3.88 (1H, m), 4.15-4.40 (1H, m), 4.55 (1H, brs),7.03-7.05 (1H, m), 7.11-7.22 (2H, m), 7.34 (1H, brs), 7.78-7.85 (1H, m),7.98-8.02 (1H, m), 8.12 (1H, brs), 9.07-9.13 (2H, m).

Example 74BN-((3S,4R)-1-((8-Methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamideA) Methyl 8-methylquinoxaline-6-carboxylate

A mixture of methyl 8-chloroquinoxaline-6-carboxylate (199 mg),2,4,6-trimethylboroxine (449 mg), a 2 M aqueous potassium carbonatesolution (0.67 mL), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex (62 mg) and DMF (20 mL) was stirredat 140° C. for 30 minutes under irradiation with microwave. Water wasadded to the reaction mixture, and the mixture was filtered throughCelite. The filtrate was subjected to extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (89.3mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.79 (3H, s), 3.96 (3H, s), 8.20 (1H, dd,J=1.7, 0.9 Hz), 8.49 (1H, d, J=1.5 Hz), 9.08 (1H, d, J=1.7 Hz), 9.09(1H, d, J=1.9 Hz).

B) 8-Methylquinoxaline-6-carboxylic acid

To a solution of methyl 8-methylquinoxaline-6-carboxylate (89.3 mg) inmethanol (1 mL) and THF (2 mL), a 1 M aqueous sodium hydroxide solution(2 mL) was added at room temperature, and the mixture was stirred atroom temperature for 2 hours. To the reaction mixture, 1 M hydrochloricacid was added at room temperature, and the solvent was distilled offunder reduced pressure. The residue was washed with water and dissolvedin ethyl acetate and toluene. The solvent was distilled off underreduced pressure to obtain the title compound (46 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.78 (3H, s), 8.18 (1H, d, J=0.8 Hz), 8.46(1H, d, J=1.5 Hz), 9.05 (1H, d, J=1.8 Hz), 9.06 (1H, d, J=1.8 Hz), 13.43(1H, brs).

C)N-((3S,4R)-1-((8-Methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamide

To a solution ofN-((3S,4R)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamidehydrochloride (80 mg), 8-methylquinoxaline-6-carboxylic acid (39 mg),HOBt (42 mg) and triethylamine (0.04 mL) in DMF (5 mL), WSC (0.06 mL)was added at 0° C., and the mixture was stirred overnight at roomtemperature. The solvent was distilled off under reduced pressure, andthe residue was diluted with water and ethyl acetate. The separatedorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(43.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.64-2.12 (2H, m), 2.79 (1H, brs), 3.32 (3H,s), 3.36 (1H, brs), 3.42-3.67 (2H, m), 3.68-4.01 (1H, m), 4.20-4.52 (1H,m), 4.63 (1H, brs), 7.04-7.48 (5H, m), 7.60-7.80 (2H, m), 7.81-8.04 (1H,m), 8.24 (1H, d, J=7.5 Hz), 8.68-8.87 (1H, m), 9.00 (2H, d, J=18.8 Hz).

Example 81BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylicacid (0.075 g), a 0.24 M solution of((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanonein DMF (1.1 mL), HOBt (0.052 g) and triethylamine (0.11 mL) in DMF (1.0mL), WSC (0.071 mL) was added at room temperature, and the mixture wasstirred for 16 hours. Water was added to the reaction mixture, followedby extraction with ethyl acetate/THF. The extract was washed with asaturated aqueous solution of potassium carbonate, water and saturatedbrine and then dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (NH, ethyl acetate/hexane) to obtainthe title compound (0.10 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.57-2.12 (2H, m), 3.34-3.48 (1H, m),3.51-3.83 (2H, m), 3.87 (3H, s), 3.91-4.10 (1H, m), 4.11-4.46 (1H, m),4.48-4.76 (1H, m), 7.07-7.45 (6H, m), 8.03 (1H, d, J=9.6 Hz), 8.13 (1H,brs), 8.46 (1H, d, J=9.0 Hz), 8.99-9.19 (2H, m).

Example 97B2-Chloro-N-(cis-1-(3,4-dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4-yl)benzamideA) Ethyl1-benzyl-5-[(trifluoromethane)sulfonyloxy]-1,2,3,6-tetrahydropyridine-4-carboxylate

To a saturated aqueous solution of sodium bicarbonate (200 mL), ethyl1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (25 g) was added,followed by extraction with ether (200 mL). This ether solution wasadded dropwise to a suspension solution of sodium hydride (60%, 6.68 g)in ether (100 mL) at 0° C., and the mixture was stirred at 0° C. for 30minutes. Trifluoromethanesulfonic anhydride (17.7 mL) was added theretoat 0° C., and the mixture was stirred for 2 hours. A saturated aqueoussolution of ammonium chloride was added to the reaction mixture at 0° C.The mixture was partitioned into the separated organic and aqueouslayers. The organic layer was washed with saturated brine and then driedover anhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (28 g).

¹H NMR (300 MHz, CDCl₃) δ 1.31 (3H, t, J=7.1 Hz), 2.57-2.59 (2H, m),2.63-2.65 (2H, m), 3.18 (2H, s), 3.63 (2H, s), 4.24-2.43 (2H, m),7.27-7.35 (5H, m).

B) Ethyl1-benzyl-5-(pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

A solution of1-benzyl-5-[(trifluoromethane)sulfonyloxy]-1,2,3,6-tetrahydropyridine-4-carboxylate(10 g), pyridine-3-boronic acid (3.2 g), potassium carbonate (7.02 g),tetrakis (triphenylphosphine)palladium (2.06 g) in DMF (20 mL) wasstirred at 90° C. for 16 hours. The reaction mixture was filteredthrough Celite and washed with ethyl acetate. The solvent in thefiltrate was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (ethyl acetate/hexane) toobtain the title compound (4.0 g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.1 Hz), 2.45-2.50 (2H, m),2.60-2.64 (2H, m), 3.22 (2H, m), 3.63 (2H, s), 3.85 (2H, q, J=7.0 Hz),7.24-7.27 (2H, m), 7.31-7.40 (3H, m), 7.56-7.62 (4H, m).

C) cis-Ethyl1-benzyl-5-(pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate

A mixture of1-benzyl-5-(pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate (1.5g), 10% palladium-carbon (200 mg), 10% palladium hydroxide-carbon (500mg), acetic acid (0.5 mL) and ethanol (60 mL) was stirred at 65° C. for48 hours in a 300 psi hydrogen atmosphere. The insoluble matter wasfiltered off, and the filtrate was concentrated under reduced pressureto obtain the title compound (800 mg).

MS: [M+H]⁺ 235.2.

D) cis-Ethyl1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidine-4-carboxylate

To a solution of(cis-1-benzyl-5-(pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxylate(5.5 g) in dichloromethane (25 mL), N,N-diisopropylethylamine (12.83 mL)was added at 0° C., followed by the addition of a solution of3,4-dimethoxybenzoyl chloride in dichloromethane (3 mL). After stirringat room temperature for 30 minutes, the mixture was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by reverse-phase HPLC to obtain the title compound (1.6 g).

MS: [M+H]⁺ 398.9.

E) 2-(Trimethylsilyl)ethylN-[cis-1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidin-4-yl]carbamate

To a solution of cis-ethyl1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidine-4-carboxylate(200 mg) in methanol (5 mL) and THF (5 mL), a solution of lithiumhydroxide (72 mg) in water (1 mL) was added at room temperature, and themixture was stirred at room temperature for 16 hours. The solvent wasdistilled off under reduced pressure, and the residue was diluted withwater. The liquid property of the solution was adjusted to near pH=4 bythe addition of 4 M hydrochloric acid. After extraction withdichloromethane, the extract was washed with water and saturated brineand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a solid. To a solution ofthe obtained solid (150 mg) in toluene (10 mL), DPPA (0.2 mL) andtriethylamine (0.2 mL) were added at room temperature, and the mixturewas stirred at 50° C. for 2 hours. Trimethylsilyl ethanol (0.75 mL) wasadded to the reaction mixture at room temperature, and the mixture wasstirred at 100° C. for 6 hours. The solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (100mg).

MS: [M+H]⁺ 486.4.

F)2-Chloro-N-(cis-1-(3,4-dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4-yl)benzamide

To a solution of 2-(trimethylsilyl)ethylN-[cis-1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidin-4-yl]carbamate(130 mg) in THF (1 mL), a 1 M solution of TBAF in THF (2 mL) was added,and the mixture was heated to reflux for 2 hours. The reaction mixturewas concentrated under reduced pressure, and the obtained residue wasdissolved in dichloromethane (5 mL). To the solution,N,N-diisopropylethylamine (0.1 mL) was added at 0° C., followed by theaddition of 2-chlorobenzoyl chloride (0.04 mL) at 0° C. After stirringat room temperature for 30 minutes, a saturated aqueous solution ofsodium bicarbonate was added thereto, followed by extraction withdichloromethane. The extract was dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to obtain the title compound (70 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.66-1.68 (1H, m), 1.90-2.07 (2H, m),3.18-3.37 (2H, m), 3.55-3.60 (1H, m), 3.78 (3H, s), 3.80 (3H, s),3.81-4.64 (2H, m), 6.98-7.10 (3H, m), 7.26-7.49 (4H, m), 7.66-7.68 (2H,m), 7.73-8.50 (3H, m).

Example 117B2-Chloro-N-(trans-1-(3,4-dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4-yl)benzamideA) 2-(Trimethylsilyl)ethylN-[trans-1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidin-4-yl]carbamate

To a solution of cis-ethyl1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidine-4-carboxylate(500 mg) in THF (10 mL), a 1 M solution of lithium diisopropylamide inTHF (3.75 mL) was added dropwise at −78° C., and the mixture was stirredat −78° C. for 4 hours. Ethanol (10 mL) was added thereto at −78° C.,and the mixture was stirred at room temperature for 10 minutes. Thesolvent was distilled off under reduced pressure to obtain a solid (420mg), and 300 mg of the obtained solid was dissolved in ethanol (6 mL)and THF (6 mL). To the solution, a solution of lithium hydroxide (90 mg)in water (1 mL) was added at room temperature, and the mixture wasstirred at room temperature for 6 hours. The solvent was distilled offunder reduced pressure, and the residue was diluted with water. Theliquid property of the solution was adjusted to near pH=5 by theaddition of 4 M hydrochloric acid. After extraction withdichloromethane, the extract was washed with water and saturated brineand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to obtain a solid. To a solution ofthe obtained solid (250 mg) in toluene (10 mL), DPPA (0.41 mL) andtriethylamine (0.35 mL) were added at room temperature, and the mixturewas stirred at 50° C. for 2 hours. Trimethylsilyl ethanol (0.75 mL) wasadded to the reaction mixture at room temperature, and the mixture wasstirred at 100° C. for 6 hours. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (210mg).

MS: [M+H]⁺ 486.0.

B)2-Chloro-N-(trans-1-(3,4-dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4-yl)benzamide

To a solution of 2-(trimethylsilyl)ethylN-[trans-1-[(3,4-dimethoxyphenyl)carbonyl]-3-(pyridin-3-yl)piperidin-4-yl]carbamate(800 mg) in THF (1 mL), a 1 M solution of TBAF in THF (3 mL) was added,and the mixture was heated to reflux for 2 hours. The reaction mixturewas concentrated under reduced pressure to obtain a residue (500 mg),and 70 mg of the obtained residue was dissolved in dichloromethane (5mL). To the solution, N,N-diisopropylethylamine (0.11 mL) was added at0° C., followed by the addition of 2-chlorobenzoyl chloride (40 mg) at0° C. After stirring at room temperature for 30 minutes, a saturatedaqueous solution of sodium bicarbonate was added thereto, followed byextraction with dichloromethane. The extract was dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to obtain the title compound (22 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.64-1.70 (1H, m), 1.79-1.84 (2H, m),2.04-2.07 (1H, m), 3.18-3.24 (2H, m), 3.81 (6H, s), 4.41-4.43 (2H, m),6.98-7.03 (4H, m), 7.27-7.35 (4H, m), 7.72-7.74 (1H, m), 7.99-8.01 (1H,m), 8.43-8.50 (2H, m).

Example 166B5-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

To a solution of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid(0.012 g),((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(0.022 g) and N-ethyldiisopropylamine (0.013 mL) in DMF (1.0 mL), HATU(0.027 g) was added at room temperature, and the mixture was stirred for90 minutes. The reaction mixture was diluted with water (1 mL), followedby extraction with ethyl acetate (3 mL). Then, ethyl acetate (2 mL) wasadded to the aqueous layer, and the reaction mixture was subjected toextraction again. The extracts were combined and concentrated by blowingat 60° C. The residue was purified by preparative high-performanceliquid chromatography (C18, mobile phase: acetonitrile/10 mM aqueousammonium bicarbonate solution) to obtain the title compound (20.4 mg).

Example 170BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

To a solution of 3-ethoxy-1-methyl-1H-pyrazole-5-carboxylic acid (0.012g), ((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone (0.022 g) and N-ethyldiisopropylamine(0.013 mL) in DMF (1.0 mL), HATU (0.027 g) was added at roomtemperature, and the mixture was stirred for 90 minutes. The reactionmixture was diluted with water (1 mL), followed by extraction with ethylacetate (3 mL). Then, ethyl acetate (2 mL) was added to the aqueouslayer, and the reaction mixture was subjected to extraction again. Theextracts were combined and concentrated by blowing at 60° C. The residuewas purified by preparative high-performance liquid chromatography (C18,mobile phase: acetonitrile/10 mM aqueous ammonium bicarbonate solution)to obtain the title compound (23.1 mg).

Example 241BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamide

To a solution of 3-(trifluoromethoxy)picolinic acid (67.5 mg),((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(99.0 mg), HOBt (51.8 mg) and triethylamine (0.113 mL) in DMF (1 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (62.9 mg) was added atroom temperature, and the mixture was stirred for 16 hours. Water wasadded to the reaction mixture, followed by extraction with ethylacetate. The extract was washed with a saturated aqueous solution ofpotassium carbonate, water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(84 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-2.12 (2H, m), 3.30-3.70 (3H, m),3.71-4.12 (1H, m), 4.18-4.52 (1H, m), 4.53-4.72 (1H, m), 7.08-7.50 (5H,m), 7.61-7.77 (1H, m), 7.93-8.17 (2H, m), 8.24 (1H, d, J=8.9 Hz),8.66-8.89 (2H, m), 9.00-9.21 (2H, m).

Example 242B6-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-4-(trifluoromethyl)nicotinamide

To a solution of((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(300 mg), 6-chloro-4-(trifluoromethyl)nicotinic acid (221 mg) andtriethylamine (0.34 mL) in DMF (1.1 mL), HATU (373 mg) was added at roomtemperature, and the mixture was stirred at room temperature for 4hours. A saturated aqueous solution of sodium bicarbonate was added tothe reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (284mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.95 (1H, m), 2.01-2.13 (1H, m),3.34-3.50 (2H, m), 3.53-3.98 (2H, m), 4.22-4.55 (1H, m), 4.56-4.67 (1H,m), 7.10-7.45 (5H, m), 7.98-8.17 (4H, m), 8.78-8.92 (1H, m), 9.02-9.19(2H, m, J=18.8 Hz).

Example 245BN-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamideA) Ethyl 3-((3-ethoxy-3-oxopropyl)amino)-2-(4-fluorophenyl)propanoate

To a solution of ethyl 2-(4-fluorophenyl)acetate (29 g) in DMF (120 mL),N,N-dimethylformamide dimethyl acetal (32 mL) was added at roomtemperature, and the mixture was stirred at 140° C. for 16 hours in anitrogen atmosphere. β-Alanine ethyl ester hydrochloride (33 g) wasadded to the reaction mixture at room temperature, and the mixture wasstirred at 80° C. for 2 hours. The solvent was distilled off underreduced pressure, and water was added thereto at room temperature,followed by extraction with ethyl acetate. The extract was washed withwater and saturated brine and then dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. To asolution of the obtained residue in DMF (300 mL) and acetic acid (300mL), sodium tetrahydroborate (36 g) was added gradually under icecooling, and the mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with ethyl acetate (150 mL), and a 2 Naqueous sodium hydroxide solution (300 mL) was added slowly under icecooling. Water (300 mL) was added to the reaction mixture, followed byextraction with ethyl acetate (100 mL, three times). The extract waswashed with a saturated aqueous solution of potassium carbonate, water(100 mL, twice) and saturated brine (100 mL) and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was dissolved in ethyl acetate (500 mL),and oxalic acid (30 mL) was added thereto at room temperature, and themixture was heated to reflux for 30 minutes. The deposit was collectedby filtration and washed with ethyl acetate. The obtained solid wassuspended in ethyl acetate and basified with an aqueous potassiumcarbonate solution, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure to obtain the title compound (26 g).

MS: [M+H]⁺ 312.1.

B) tert-Butyl 3-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate

To a solution of ethyl3-((3-ethoxy-3-oxopropyl)amino)-2-(4-fluorophenyl)propanoate (26 g) inTHF (250 mL), 60% sodium hydride (60%, 11 g) was added under icecooling, and the mixture was heated to reflux for 30 minutes in anitrogen atmosphere. Water (250 mL) was added to the reaction mixture,followed by extraction with ethyl acetate (250 mL, 100 mL, three times).The extract was washed with saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. A mixture of the obtained residue, concentratedhydrochloric acid (110 mL) and acetic acid (110 mL) was heated to refluxfor 16 hours. The solvent was distilled off under reduced pressure.

To a solution of the obtained residue and triethylamine (35 mL) in THF(200 mL), di-tert-butyl dicarbonate (19 mL) was added at roomtemperature, and the mixture was stirred for 30 minutes. Water was addedto the reaction mixture, followed by extraction with ethyl acetate. Theextract was washed with water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (15g).

MS: [M+H−Boc]⁺194.1.

C) (3S,4R)-tert-Butyl3-(4-fluorophenyl)-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate

To a solution of tert-butyl3-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate (11 g) and(R)-1-phenylethanamine (6.1 mL) in toluene (120 mL), aluminum chloride(0.34 g) was added, and the mixture was heated to reflux for 16 hours ina nitrogen atmosphere. The solvent was distilled off under reducedpressure. A mixture of the obtained residue, a developed nickel catalyst(2.1 g) and ethanol (55 mL) was stirred at room temperature for 24 hoursin a hydrogen atmosphere (0.5 MPa). The reaction mixture was filtered,and the solvent in the filtrate was distilled off under reducedpressure. The residue was suspended in toluene, and the solid wasfiltered off. The solvent in the filtrate was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (2.4g).

MS: [M+H]⁺ 399.1.

D) (3S,4R)-tert-Butyl 4-amino-3-(4-fluorophenyl)piperidine-1-carboxylate

A mixture of (3S,4R)-tert-butyl3-(4-fluorophenyl)-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate(2.4 g), 10% palladium-carbon (1.1 g), methanol (30 mL) and acetic acid(3 mL) was stirred at room temperature for 6 hours in a hydrogenatmosphere (1 atm). The reaction mixture was filtered, and the solventin the filtrate was distilled off under reduced pressure. The residuesolid was collected by filtration and washed with hexane to obtain thetitle compound (0.95 g).

MS: [M+H−100]⁺238.9.

E) (3S,4R)-tert-Butyl3-(4-fluorophenyl)-4-(3-(trifluoromethyl)picolinamido)piperidine-1-carboxylate

To a solution of 3-(trifluoromethyl)picolinic acid (0.41 g),(3S,4R)-tert-butyl 4-amino-3-(4-fluorophenyl)piperidine-1-carboxylate(0.53 g) and HOBt (0.37 g) in DMF (10 mL), WSC (0.47 mL) was added underice cooling, and the mixture was stirred at room temperature for 3hours. The solvent was distilled off under reduced pressure, and waterwas added to the reaction mixture, followed by extraction with ethylacetate. The extract was washed with saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to obtain the title compound (0.74g).

MS: [M+H−100]+368.0.

F)N-((3S,4R)-1-((8-Chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)-3-(trifluoromethyl)pyridine-2-carboxamide

To (3S,4R)-tert-butyl3-(4-fluorophenyl)-4-(3-(trifluoromethyl)picolinamido)piperidine-1-carboxylate(0.73 g), a 4 M solution of hydrogen chloride in ethyl acetate (50 mL)was added under ice cooling, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distilled off under reducedpressure to obtainN-((3S,4R)-3-(4-fluorophenyl)piperidin-4-yl)-3-(trifluoromethyl)picolinamidehydrochloride (0.64 g). To a solution of8-chloroquinoxaline-6-carboxylic acid (0.063 g),N-((3S,4R)-3-(4-fluorophenyl)piperidin-4-yl)-3-(trifluoromethyl)picolinamidehydrochloride (0.10 g), HOBt (0.061 g) and triethylamine (0.17 mL) inDMF (1.0 mL), WSC (0.066 mL) was added at room temperature, and themixture was stirred for 16 hours. Water was added to the reactionmixture, followed by extraction with ethyl acetate. The extract waswashed with a saturated aqueous solution of potassium carbonate, waterand saturated brine and then dried over anhydrous magnesium sulfate, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane),and the obtained solid was washed with diisopropyl ether to obtain thetitle compound (0.079 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.58-2.16 (2H, m), 3.34-3.70 (3H, m),3.72-4.00 (1H, m), 4.10-4.51 (1H, m), 4.54-4.66 (1H, m), 6.94-7.31 (3H,m), 7.32-7.51 (1H, m), 7.70 (1H, dd, J=7.3, 5.1 Hz), 8.01 (1H, d, J=11.5Hz), 8.12 (1H, brs), 8.24 (1H, d, J=7.5 Hz), 8.74-8.89 (2H, m), 9.10(2H, d, J=18.6 Hz).

Example 246B3-Chloro-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)pyridine-2-carboxamide

To a solution of 3-chloropicolinic acid (62.4 mg),((3S,4R)-4-amino-3-phenylpiperidin-1-yl)(8-chloroquinoxalin-6-yl)methanone(99.0 mg), HOBt (57 mg) and triethylamine (0.113 mL) in DMF (1 mL),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (62.9 mg) was added atroom temperature, and the mixture was stirred for 16 hours. Water wasadded to the reaction mixture, followed by extraction with ethylacetate. The extract was washed with a saturated aqueous solution ofpotassium carbonate, water and saturated brine and then dried overanhydrous magnesium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to obtain the title compound(82 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.62-2.17 (2H, m), 3.33-3.69 (3H, m),3.71-4.06 (1H, m), 4.14-4.54 (1H, m), 4.56-4.74 (1H, m), 7.07-7.42 (5H,m), 7.48 (1H, dd, J=8.2, 4.6 Hz), 7.95 (1H, dd, J=8.3, 1.3 Hz), 8.02(1H, d, J=10.2 Hz), 8.13 (1H, brs), 8.46-8.54 (1H, m, J=4.6, 1.2 Hz),8.65-8.83 (1H, m), 8.99-9.21 (2H, m).

Example 253BN-(trans-1′-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1,3′-bipiperidin-4′-yl)-2-(trifluoromethoxy)benzamideA) trans-tert-Butyl 4-azido-3-hydroxypiperidine-1-carboxylate

A solution of a crude product of tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7.0 g), sodium azide(3.4 g) and ammonium chloride (2.8 g) in ethanol (80 mL) and water (80mL) was stirred at 80° C. for 6 hours. Water was added to the reactionmixture at room temperature, followed by extraction with ethyl acetate.The extract was dried over anhydrous magnesium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (petroleum ether/ethyl acetate) toobtain the title compound (5.5 g).

MS: [M+H−100]⁺143.1.

B) trans-tert-Butyl3-hydroxy-4-(2-(trifluoromethoxy)benzamido)piperidine-1-carboxylate

A mixture of trans-tert-butyl 4-azido-3-hydroxypiperidine-1-carboxylate(11 g), 10% palladium-carbon (1.1 g) and methanol (100 mL) was stirredat room temperature for 4 hours in a hydrogen atmosphere (1 atm). Thereaction mixture was filtered, and the solvent in the filtrate wasdistilled off under reduced pressure. To a solution of the obtainedresidue, 2-(trifluoromethoxy)benzoic acid (9.0 g) and triethylamine (13g) in DMF (50 mL), HATU (25 g) was added at room temperature, and themixture was stirred for 12 hours. The solvent was distilled off underreduced pressure, and the residue was purified by silica gel columnchromatography (petroleum ether/hexane) to obtain the title compound (14g).

MS: [M+H−56]⁺349.1.

C)N-(trans-1-(5,6-Dimethoxynicotinoyl)-3-hydroxypiperidin-4-yl)-2-(trifluoromethoxy)benzamide

To trans-tert-butyl3-hydroxy-4-(2-(trifluoromethoxy)benzamido)piperidine-1-carboxylate (14g), a 4 M solution of hydrogen chloride in ethyl acetate (70 mL) wasadded at room temperature, and the mixture was stirred at roomtemperature for 6 hours. The solvent was distilled off under reducedpressure to obtainN-((3RS,4RS)-3-hydroxypiperidin-4-yl)-2-(trifluoromethoxy)benzamidehydrochloride. To a solution of the obtainedN-(trans-3-hydroxypiperidin-4-yl)-2-(trifluoromethoxy)benzamidehydrochloride (6.0 g), 5,6-dimethoxynicotinic acid (3.3 g) andtriethylamine (5.3 g) in DMF (30 mL), HATU (10 g) was added at roomtemperature, and the mixture was stirred for 12 hours. The solvent wasdistilled off under reduced pressure, and the residue was purified byreverse-phase HPLC to obtain the title compound (4.0 g).

MS: [M+H]⁺ 470.2.

D)N-(trans-1′-((5,6-Dimethoxypyridin-3-yl)carbonyl)-1,3′-bipiperidin-4′-yl)-2-(trifluoromethoxy)benzamide

A mixture ofN-(trans-1-(5,6-dimethoxynicotinoyl)-3-hydroxypiperidin-4-yl)-2-(trifluoromethoxy)benzamide(0.94 g), methanesulfonyl chloride (0.69 g), triethylamine (0.61 g) anddichloromethane (10 mL) was stirred at room temperature for 1 hour. Anaqueous sodium bicarbonate solution was added to the reaction mixture,followed by extraction with dichloromethane. The extract was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to obtain(3RS,4RS)-1-(5,6-dimethoxynicotinoyl)-4-(2-(trifluoromethoxy)benzamido)piperidin-3-ylmethanesulfonate. To a solution of the obtainedtrans-1-(5,6-dimethoxynicotinoyl)-4-(2-(trifluoromethoxy)benzamido)piperidin-3-ylmethanesulfonate (0.25 g) in acetonitrile (5.0 mL), piperidine (0.078 g)and cesium carbonate (0.30 g) were added at room temperature, and themixture was stirred at room temperature for 14 hours. The solvent wasdistilled off under reduced pressure, and the residue was purified bypreparative TLC to obtain the title compound (0.060 g).

¹H NMR (400 MHz, CDCl₃) δ 1.38-1.58 (7H, m), 2.43-2.55 (3H, m),2.74-2.77 (5H, m), 3.91-4.90 (9H, m), 7.18 (2H, d, J=2.0 Hz), 7.32 (1H,d, J=8.4 Hz), 7.39-7.43 (1H, m), 7.50-7.54 (1H, m), 7.80 (1H, d, J=2.0Hz), 7.98-8.00 (1H, m).

Example 255BN-((3S,4R)-1-(5-Cyano-6-methoxynicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamideA) (3S,4R)-tert-Butyl3-phenyl-4-(2-(trifluoromethoxy)benzamido)piperidine-1-carboxylate

To a solution of tert-butyl(3S,4R)-4-amino-3-phenylpiperidine-1-carboxylate (5.00 g) in pyridine(50 mL), 2-(trifluoromethoxy)benzoyl chloride (4.88 g) was added underice cooling, and the mixture was stirred at room temperature for 2hours. The solvent was distilled off under reduced pressure, and theresidue was diluted with a saturated aqueous solution of sodiumbicarbonate, followed by extraction with ethyl acetate. The extract waswashed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to obtain the title compound (1.80 g).

¹H NMR (300 MHz, CDCl₃) δ 1.45 (9H, brs), 1.85-2.03 (2H, m), 3.13-3.29(1H, m), 3.30-3.69 (2H, m), 3.79-4.12 (2H, m), 4.52-4.72 (1H, m),6.15-6.43 (1H, m), 7.26 (7H, s), 7.41-7.51 (1H, m), 7.79-7.87 (1H, m).

B) N-((3S,4R)-3-Phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamidehydrochloride

To a solution of (3S,4R)-tert-butyl3-phenyl-4-(2-(trifluoromethoxy)benzamido)piperidine-1-carboxylate (1.79g) in methanol (3 mL), a 4 M solution of hydrogen chloride incyclopentyl methyl ether (9.63 mL) was added at room temperature, andthe mixture was stirred at room temperature for 2 hours. The solvent wasdistilled off under reduced pressure, and the residue was washed withdiisopropyl ether to obtain the title compound (1.30 g).

MS: [M+H]⁺ 365.0.

C)N-((3S,4R)-1-(5-Bromo-6-chloronicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

To a solution ofN-((3S,4R)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamidehydrochloride (267.2 mg), 5-bromo-6-chloronicotinic acid (173 mg) andtriethylamine (0.278 ml) in dry DMF (3.0 ml), HATU (330 mg) was added atroom temperature, and the mixture was stirred for 30 minutes. Water wasadded to the reaction mixture, and the resulting solid was collected byfiltration and washed with water. The solid was further purified bysilica gel column chromatography (ethyl acetate/hexane) and thencrystallized from ethyl acetate/hexane to obtain the title compound (317mg).

MS: [M+H]⁺ 582.0

D)N-((3S,4R)-1-(5-Bromo-6-methoxynicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

To a solution of methanol (0.017 ml) in dry THF (1.5 ml), sodium hydride(60%, 17.02 mg) was added at 0° C., and then, the mixture was stirred at0° C. for 40 minutes.N-((3S,4R)-1-(5-Bromo-6-chloronicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide(80 mg) was added to the reaction mixture, and then, the mixture wasstirred at room temperature for 1 hour in a nitrogen atmosphere. Asaturated aqueous solution of ammonium chloride was added to thereaction mixture at 0° C., followed by extraction with ethyl acetate.The extract was washed with saturated brine and then dried overanhydrous sodium sulfate, and the solvent was distilled off. The residuewas crystallized from ethyl acetate/hexane to obtain the title compound(37.9 mg).

MS: [M+H]⁺ 578.0

E)N-((3S,4R)-1-(5-Cyano-6-methoxynicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

A mixture ofN-((3S,4R)-1-(5-bromo-6-methoxynicotinoyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide(69 mg), tris(dibenzylideneacetone)dipalladium),2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (19.59 mg), zinccyanide (28.0 mg), dry DMF (1.2 ml) and water (0.012 ml) was stirred at120° C. for 20 minutes under irradiation with microwave. The reactionmixture was added to water at room temperature, followed by extractionwith ethyl acetate. The extract was washed with saturated brine and thendried over anhydrous sodium sulfate, and the solvent was distilled off.The residue was purified by silica gel column chromatography (ethylacetate/hexane) and then crystallized from ethyl acetate/diisopropylether to obtain the title compound (7.60 mg).

¹H NMR (300 MHz, DMSO) δ 1.54-1.89 (1H, m), 1.91-2.04 (1H, m), 3.17-3.39(1H, m), 3.40-3.67 (2H, m), 3.69-3.93 (1H, m), 4.02 (3H, brs), 4.12-4.42(1H, m), 4.53-4.63 (1H, m), 7.07-7.15 (1H, m), 7.17-7.44 (7H, m),7.48-7.58 (1H, m), 8.22-8.66 (3H, m).

Example 412BN-((3S,4R)-1-((8-Methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamideA) tert-Butyl(3S,4R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbonyl)amino)-3-phenylpiperidine-1-carboxylate

To a solution of tert-butyl(3S,4R)-4-amino-3-phenylpiperidine-1-carboxylate (3.00 g),1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (2.53 g) andHOBt (2.20 g) in DMF (40 mL), WSC (2.86 mL) was added under ice cooling,and the mixture was stirred overnight at room temperature. The solventwas distilled off under reduced pressure, and water was added to thereaction mixture, followed by extraction with ethyl acetate. The extractwas washed with saturated brine and then dried over anhydrous sodiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to obtain the title compound (4.42 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.41 (9H, brs), 1.60-1.91 (2H, m), 3.14 (1H,d, J=3.6 Hz), 3.37-3.51 (1H, m), 3.58-3.87 (3H, m), 3.90 (3H, s), 4.49(1H, brs), 6.80-7.47 (6H, m), 8.31 (1H, d, J=8.9 Hz).

B)N-((3S,4R)-3-Phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride

To tert-butyl(3S,4R)-4-(((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)carbonyl)amino)-3-phenylpiperidine-1-carboxylate(4.42 g), a 4 M solution of hydrogen chloride in ethyl acetate (50 mL)was added under ice cooling, and the mixture was stirred at roomtemperature for 3 hours. The solvent was distilled off under reducedpressure to obtain the title compound (3.81 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.87 (1H, d, J=12.6 Hz), 2.23 (1H, ddd,J=14.1, 10.1, 4.1 Hz), 3.13-3.34 (3H, m), 3.45 (1H, dt, J=13.4, 3.9 Hz),3.83 (3H, s), 4.05 (1H, t, J=13.0 Hz), 4.66 (1H, dd, J=9.7, 3.1 Hz),7.08-7.34 (5H, m), 7.40 (1H, s), 8.75 (1H, d, J=9.8 Hz), 9.08 (1H, brs),9.65 (1H, brs).

C)N-((3S,4R)-1-((8-Methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

To a solution ofN-((3S,4R)-3-phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamidehydrochloride (200 mg), 8-methoxyquinoxaline-6-carboxylic acid (105 mg),HOBt (104 mg) and triethylamine (0.11 mL) in DMF (5 mL), WSC (0.14 mL)was added at room temperature, and the mixture was stirred overnight atroom temperature. The reaction mixture was diluted with water and ethylacetate. The separated organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure. The residue was purified by silica gelcolumn chromatography (methanol/ethyl acetate) to obtain the titlecompound (231.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.63-2.11 (2H, m), 3.35-3.45 (1H, m),3.49-3.78 (2H, m), 3.88 (3H, s), 3.92-4.12 (4H, m), 4.13-4.50 (1H, m),4.62 (1H, brs), 7.02-7.43 (7H, m), 7.49-7.72 (1H, m), 8.45 (1H, d, J=8.7Hz), 8.95 (2H, t, J=19.4 Hz).

Compounds of Examples 4A to 10A, 12A to 16A, 19A to 29A, 31A to 35A, 37Ato 40A, 43A to 53A, 55A to 73A, 76A to 92A, 95A, 97A to 112A, 114A to116A, 119A to 125A, 127A to 131A, 134A to 142A, 144A to 147A, 149A to152A, 154A, 156A to 159A, 161A, 163A, 164A, 166A to 169A, 173A to 177A,179A to 186A, 188A, 191A, 195A, 197A to 200A, 202A, 203A, 205A to 216A,218A, 1B to 3B, 5B to 22B, 25B to 30B, 32B to 41B, 43B, 44B, 46B, 49B to54B, 56B to 58B, 60B to 73B, 75B to 80B, 82B to 96B, 98B to 116B, 118Bto 165B, 167B to 169B, 171B to 210B, 213B, 214B, 216B to 219B, 221B to240B, 243B, 244B, 247B to 252B, 254B, 256B to 411B, and 413B to 462B intables below were produced according to the methods described in theabove Examples or methods equivalent thereto. The compounds of Examplesare shown in tables below. In the tables, MS is indicated by actuallymeasured values.

TABLE 1 Ex. No. IUPAC Name Structure Salt MS  1A 2-chloro-N-(4-(3,4-dimethoxybenzoyl)-2-methyl- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

455.1  2A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

455.1  3A 2-chloro-N-(7-(3,4- dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo [3,4-b]pyridin-4-yl)benzamide

455.0  4A 2-chloro-N-(4-((1,3-dimethyl- 1H-pyrazol-5-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

413.1  5A 2-chloro-N-(4-((6- chloropyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

430.0  6A 2-chloro-N-(1-methyl-4-((6- (trifluoromethyl)pyridin-3-yl)carbonyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7- yl)benzamide

464.1  7A N-(4-(1-benzothiophen-5- ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2- chlorobenzamide

451.0  8A 2-chloro-N-(4-(4- (dimethylamino)benzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

438.1  9A 2-chloro-N-(1-methyl-4-(4-(5- methyl-1,2,4-oxadiazol-3-yl)benzoyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7- yl)benzamide

477.7  10A 2-chloro-N-(4-((6- methoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7- yl)benzamide

426.1  12A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-2-(4-methoxybenzyl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

561.2  13A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b] pyridin-7-yl)benzamide

441.1  14A 2-chloro-N-(2- (cyclopropylmethyl)-4-(3,4-dimethoxybenzoyl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

495.1  15A 2-chloro-N-(2-methyl-4- (quinoxalin-6-ylcarbonyl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

447.1  16A 2-chloro-N-(4-(3,5- diisopropoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

511.2  17A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2] oxazolo[4,3-b]pyridin-7-yl) benzamide

456.1  18A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-((3-methyloxetan-3-yl)methyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

525.2  19A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-2-((3-methyloxetan-3-yl)methyl)- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

525.2  20A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-2-(2,2-dimethylpropyl)-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

511.2  21A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-2-(tetrahydro-2H-pyran-4-yl)- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

525.2  22A 2-chloro-N-(4-(3,5- dimethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

455.1  23A 2-chloro-N-(4-(3,4- diethoxybenzoyl)-2-methyl-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

483.1  24A N-(4-(3,4-dimethoxybenzoyl)- 2-(4-methoxybenzyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b] pyridin-7-yl)-2- methylbenzamide

541.3  25A 2-chloro-N-(4-((2,6- dimethoxypyridin-3-yl)carbonyl)-2-methyl-4,5,6,7- tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

456.1  26A N-(4-(3,4-dimethoxybenzoyl)- 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)-2- methylbenzamide

421.2  27A N-(4-(3,4-dimethoxybenzoyl)- 2-ethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7-yl)- 2-methylbenzamide

449.2  28A N-(4-(3,4-dimethoxybenzoyl)- 2-propyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7- yl)-2-methylbenzamide

463.2  29A N-(4-(3,4-dimethoxybenzoyl)- 2-isopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-7- yl)-2-methylbenzamide

463.2  30A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro[1,2]thiazolo[4,3-b] pyridin-7-yl)benzamide

458.1  31A N-(4-(3,4-dimethoxybenzoyl)- 2-(2-methoxyethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b] pyridin-7-yl)-2- methylbenzamide

479.2  32A N-(2-(2-amino-2-oxoethyl)-4- (3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-2H- pyrazolo[4,3-b]pyridin-7-yl)-2- methylbenzamide

478.2  33A 2-chloro-N-(4-(3,4- dichlorobenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

463.0  34A 2-chloro-N-(4-(3-chloro-4- methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

459.1  35A 2-chloro-N-(4-(4-chloro-3- methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

459.1  36A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7- yl)benzamide

483.1  37A 2-chloro-N-(4-(3,5- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

455.1  38A 2-chloro-N-(4-(3,5- difluorobenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

431.0  39A 2-chloro-N-(4-(3,4- difluorobenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

431.0  40A 2-chloro-N-(1-methyl-4- (pyridazin-4-ylcarbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

397.1  43A N-(4-(1,3-benzothiazol-5- ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2- chlorobenzamide

452.0  44A 2-chloro-N-(4-(4-cyanobenzoyl)- 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

420.1  45A 2-chloro-N-(4-(3-cyanobenzoyl)- 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

420.1  46A 2-chloro-N-(1-methyl-4-(4- (methylsulfonyl)benzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

473.1  47A 2-chloro-N-(4-(3-chloro-4- (methylsulfonyl)benzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

507.0  48A 2-chloro-N-(1-methyl-4-(3- (methylsulfonyl)benzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

473.1  49A 2-chloro-N-(4-(4-chloro-3- (methylsulfonyl)benzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

507.0  50A 2-chloro-N-(4-(3-chloro-4- (trifluoromethyl)benzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

497.0  51A 2-chloro-N-(1-methyl-4- (pyrimidin-4-ylcarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)benzamide

397.1  52A 2-chloro-N-(1-methyl-4-(3,4,5- trifluorobenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)benzamide

446.9  53A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- fluorobenzamide

439.1  54A N-(3-bromo-4-(3-chloro-4- methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2- chlorobenzamide

536.9  55A 3-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

455.1  56A 4-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

455.1  57A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

421.1  58A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-3- fluorobenzamide

439.1  59A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-4- fluorobenzamide

439.1  60A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) pyridine-2-carboxamide

422.1  61A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) nicotinamide

422.1  62A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) thiophene-2-carboxamide

427.1  63A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-1,3- thiazole-2-carboxamide

428.1  64A 3-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)thiophene-2-carboxamide

461.1  65A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- furamide

411.2  66A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl) isonicotinamide

422.1  67A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-3- (trifluoromethyl)benzamide

489.1  68A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-4- (trifluoromethyl)benzamide

489.1  69A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethyl)benzamide

489.1  70A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-3- methoxybenzamide

451.1  71A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-4- methoxybenzamide

451.1  72A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- methoxybenzamide

451.1  73A 2-chloro-N-(4-(3-methoxy-5- (trifluoromethoxy)benzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

509.1  74A 2-chloro-N-((7S)-4-(3,4- dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

483.1  75A 2-chloro-N-((7R)-4-(3,4- dimethoxybenzoyl)-1-isopropyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

483.1  76A N-(4-benzoyl-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- chlorobenzamide

395.1  77A 2-chloro-N-(4-(4- methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

425.0  78A N-(4-(3-chloro-4- methoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

493.1  79A 2-chloro-N-(4-((5,6- dimethoxypyridin-2-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

456.1  80A 2-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

456.0  81A 2-chloro-N-(4-(2- methoxyisonicotinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

426.2  82A 2-chloro-N-(4-(2- chloroisonicotinoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

430.0  83A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-(2,2,2-trifluoroethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

523.1  84A 2-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

460.1  85A N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

492.1  86A 2,6-dichloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

489.1  87A 2,3-dichloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-teterahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

489.0  88A 2,4-dichloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

489.1  89A 2,5-dichloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

489.1  90A 4-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

521.0  91A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-4- (trifluoromethyl)nicotinamide

490.1  92A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)nicotinamide

456.1  95A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-1- naphthamide

471.2  97A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- naphthamide

471.2  98A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

505.1  99A 2-cyano-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

446.1 100A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

487.9 101A 3-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)pyridine-2-carboxamide

456.1 102A 2-(difluoromethoxy)-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

487.1 103A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethyl)nicotinamide

490.1 104A 3-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl) isonicotinamide

456.1 105A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-1- benzofuran-7-carboxamide

461.1 106A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2,3- dihydro-1-benozfuran-7- carboxamide

463.1 107A 5-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-1,3-benzodioxole-4-carboxamide

499.1 108A N-(4-(3,4-dimethoxybenzoyl)-1- methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (methylsulfonyl)benzamide

499.1 109A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

469.2 110A N-(1-butyl-4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2- chlorobenzamide

497.2 111A 2-chloro-N-(1-cyclopentyl-4- (3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)benzamide

509.2 112A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

483.0 113A 2-chloro-N-(3-chloro-4-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

488.9 114A 4-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

527.9 115A 2-chloro-N-(4-(3-chloro-4- methoxybenzoyl)-1-cyclopentyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

513.0 116A 2-chloro-N-(1-cyclopentyl-4- ((5,6-dimethoxypyridin-3-yl)carbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

510.1 117A 2-chloro-N-(7-(3,4- dimethoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]thiazolo [5,3-b]pyridin-4-yl)benzamide

472.0 118A 2-chloro-N-(7-(3-chloro-4- methoxybenzoyl)-3-methyl-4,5,6,7-tetrahydro[1,2]thiazolo [5,4-b]pyridin-4-yl)benzamide

476.0 119A 2-chloro-N-(4-(imidazo[1,2-a] pyridin-6-ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

435.0 120A 2-chloro-N-(4-(imidazo[1,2-a] pyridin-2-ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

435.0 121A 4-chloro-N-(4-(imidazo[1,2-a] pyridin-2-ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzmaide

503.0 122A 2-chloro-N-(1-(2,2- difluoroethyl)-4-(3,4-dimethoxybenzoyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

505.0 123A 4-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

552.0 124A 2-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

484.1 125A 2-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

510.0 126A 4-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl) benzamide

577.9 127A 4-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

524.0 128A 2-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

484.1 129A N-(4-((5,6-dimethoxypyridin-3- yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

534.1 130A 2-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

488.0 131A 4-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

556.0 132A N-(4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

534.1 133A N-(4-((5,6-dimethoxypyridin-3- yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

506.0 134A 4-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

556.0 135A 2-chloro-N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

488.0 136A N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

538.0 137A 2-chloro-N-(1-methyl-4-((1- methyl-1H-benzimidazol-5-yl)carbonyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl) benzamide

449.0 138A N-(4-(1,3-benzothiazol-6- ylcarbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2- chlorobenzamide

451.9 139A 2-chloro-N-(1-(2,2- difluoroethyl)-4-((5,6-dimethoxypyridin-3-yl)carbonyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

506.0 140A 2-chloro-N-(1-(2,2- difluoroethyl)-4-((5,6-dimethoxypryidin-3-yl)carbonyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-4- fluorobenzamide

524.0 141A 4-chloro-N-(1-(2,2- difluoroethyl)-4-((5,6-dimethoxypyridin-3-yl)carbonyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethyl)benzamide

574.0 142A N-(1-(2,2-difluoroethyl)-4-((5,6-dimethoxypyridin-3-yl)carbonyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

556.0 144A 2-chloro-N-(4-((5,6- dichloropyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

463.9 145A N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-(2,2-difluoroethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

559.9 146A 2-chloro-N-(4-((5-chloro-6- (cyclohexyloxy)pyridin-3-yl)carbonyl)-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

528.0 147A 2-chloro-N-(4-((5-chloro-6- isopropoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

486.0 149A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-(2-methoxyethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

499.0 150A 2-chloro-N-(4-((5-chloro-6-(2- hydroxyethoxy)pyridin-3-yl)carbonyl)-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

490.1 151A 2-chloro-N-(4-((5-chloro-6- (methylamino)pyridin-3-yl)carbonyl)-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

459.2 152A 2-chloro-N-(4-((5-chloro-6- (dimethylamino)pyridin-3-yl)carbonyl)-1-methyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

473.0 153A 4-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

538.1 154A 2-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

470.1 155A N-(4-((5,6-dimethoxypyridin-3- yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

520.2 156A N-(4-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

538.1 157A 4-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-isobutyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

566.1 158A N-(4-((5,6-dimethoxypyridin-3-yl)carbonyl)-1-isobutyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

548.2 159A (N-((7R)-4-(3,4- dimethoxybenzoyl)-1-(5-((3-(4,4-difluoro-5,7-dimethyl-3a- azonia-4-bora(IV)-4H-4a-aza-s-indacene-3- yl)propanoyl)amino)pentyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

850.2 160A (N-((7S)-4-(3,4- dimethoxybenzoyl)-1-(5-((3-(4,4-difluoro-5,7-dimethyl-3a- azonia-4-bora(IV)-4H-4a-aza-s-indacene-3- yl)propanoyl)amino)pentyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

850.3 161A (N-(4-(3,4- dimethoxybenzoyl)-1-(5-((3-(4,4-difluoro-5,7-dimethyl-3a- azonia-4-bora(IV)-4H-4a-aza-s-indacene-3- yl)propanoyl)amino)pentyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

850.3 162A N-((7S)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

534.2 163A N-((7S)-1-isopropyl-4-((5- methoxy-6-oxo-1,6-dihydropyridin-3-yl)carbonyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

520.2 164A 4-chloro-N-((7R)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

538.1 165A 4-chloro-N-((7S)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

538.1 166A N-((7S)-4-((6-(difluoromethoxy)- 5-methoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

570.2 167A N-(1-cyclobutyl-4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

545.2 168A N-(4-(3,4-dimethoxybenzoyl)-1-(1-(2,2,2-trifluoroethyl)acetidin- 3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2- (trifluoromethoxy)benzamide

628.4 169A N-(4-((5,6-dimethoxypyridin-3- yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

494.0 170A 4-chloro-N-((7S)-4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)- 1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethyl)benzamide

578.1 171A N-((7S)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

506.2 172A 2-chloro-N-(7-(3,4- dimethoxybenzoyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H- pyrazolo[3,4-b]pyridin-4-yl) benzamide

469.2 173A tert-butyl (5-(4-(3,4- dimethoxybenzoyl)-7-((2-(trifluoromethoxy)benzoyl) amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl) pentyl)carbamate

676.4 174A N-(1-(cyclopropylmethyl)-4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

545.2 175A N-(4-(3,4-dimethoxybenzoyl)-1- ((1-fluorocyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

563.1 176A N-(1-(5-aminopentyl)-4-(3,4- dimethoxybenzoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethoxy)benzamide

2HCl 576.2 177A N-((7R)-4-(5,6- dimethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

506.2 178A N-((7S)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

520.2 179A N-((7R)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-ethyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

520.2 180A N-((7R)-4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

534.1 181A 9H-fluoren-9-ylmethyl (5-(4- (3,4-dimethoxybenzoyl)-7-((2-(trifluoromethoxy)benzoyl) amino)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridin-1-yl) pentyl)carbamate

798.4 182A 2-chloro-N-(4-((5-chloro-6- ethoxypyridin-3-yl)carbonyl)-1-methyl-4,5,6,7-tetrahydro-1H- pyrazolo[4,3-b]pyridin-7-yl) benzamide

473.9 183A 4-chloro-N-(4-((5-chloro-6-oxo- 1,6-dihydropyridin-3-yl)carbonyl)-1-isopropyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl) benzamide

542.1 184A 4-chloro-N-((7R)-4-((5-chloro-6-methoxypyridin-3-yl)carbonyl)- 1-(2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b] pyridin-7-yl)-2-(trifluoromethyl)benzamide

578.1 185A 4-chloro-N-(4-((5,6- dimethoxypyridin-3-yl)carbonyl)-1-propyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-b]pyridin-7-yl)-2-(trifluoromethyl)benzamide

552.1 186A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-(3-hydroxy-3-methylbutyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3-b]pyridin-7-yl)benzamide

527.2 188A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-octadecyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

693.4 191A 2-chloro-N-(4-(3,4- dimethoxybenzoyl)-1-isobutyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)benzamide

497.2 192A N-(4-((5,6-dimethoxypyridin-3- yl)carbonyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-b]pyridin-7-yl)-2-(trifluoromethoxy)benzamide

520.2 193A 2-chloro-N-(7-(3,4- dimethoxybenzoyl)-1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-b]pyridin-4-yl)benzamide

455.1 195A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

451.1 197A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)pyridine- 2-carboxamide

CF3COOH 452.0 198A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) thiophene-2-carboxamide

457.0 199A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)-1,3- thiazole-2-carboxamide

458.0 200A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)-4- methoxybenzamide

481.1 201A 2-chloro-N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

485.1 202A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)-4- (trifluoromethyl)benzamide

519.1 203A N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl)-6- (trifluoromethyl)nicotinamide

CF3COOH 518.1 204A 2-chloro-N-(1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

451.1 205A N-(1-benzoyl-7-chloro-1,2,3,4- tetrahydroquinolin-4-yl)-2-chlorobenzamide

425.0 206A 2-chloro-N-(7-chloro-1-(4- (trifluoromethoxy)benzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

509.1 207A 2-chloro-N-(7-chloro-1-(2- furoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

414.9 208A 2-chloro-N-(7-chloro-1-(1,2- oxazol-5-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

416.0 209A 2-chloro-N-(7-chloro-1-(pyridin- 3-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

CF3COOH 426.0 210A 2-chloro-N-(7-chloro-1-(1,3-thiazol-2-ylcarbonyl)-1,2,3,4- tetrahydroquinolin-4-yl) benzamide

432.0 211A 2-chloro-N-(7-chloro-1-((1,3- dimethyl-1H-pyrazol-5-yl)carbonyl)-1,2,3,4- tetrahydroquinolin-4-yl) benzamide

443.1 212A 2-chloro-N-(7-chloro-1-(4- fluorobenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

443.1 213A 2-chloro-N-(7-chloro-1-(pyridin- 3-ylcarbonyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

426.0 214A 2-chloro-N-(7-chloro-1-(4- methoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

455.1 215A 2-chloro-N-(7-chloro-1-(3- methoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

455.1 216A 2-chloro-N-(7-chloro-1-(2- methoxybenzoyl)-1,2,3,4-tetrahydroquinolin-4-yl) benzamide

455.1 217A 2-chloro-N-(7-chloro-1-(3,4- dimethoxybenzoyl)-1,2,3,4-tetrahydro-1,8-naphthyridin-4- yl)benzamide

486.1 218A 2-chloro-N-(7-chloro-1-((6- chloropyridin-3-yl)carbonyl)-1,2,3,4-tetrahydro-1,8- naphthyridin-4-yl)benzamide

461.1

TABLE 2-1 Ex. No. IUPAC Name Structure Salt MS  1B2-chloro-N-((3R,4S)-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

479.0  2B 2-chloro-N-((3S,4R)-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

479.0  3B 2-chloro-N-((3R,4R)-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

479.0  4B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

479.0  5B 2-chloro-N-((3R,4R)-3-(3,4- dichlorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

546.8  6B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(4-methylphenyl)piperidin-4- yl)benzamide

493.1  7B 2-chloro-N-(trans-3-(4- chlorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

512.9  8B 2-chloro-N-(trans-3-(3,5- dichlorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

546.9  9B 2-chloro-N-(trans-3-(3- chloro-4-fluorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin- 4-yl)benzamide

531.0  10B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(4-methoxyphenyl)piperidin-4-yl) benzamide

509.1  11B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(4-fluorophenyl)piperidin-4- yl)benzamide

497.0  12B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(4-fluoro-3-methylphenyl)piperidin- 4-yl)benzamide

511.0  13B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(3-fluoro-4-methylphenyl)piperidin- 4-yl)benzamide

511.0  14B 2-chloro-N-(trans-3-(3- chlorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

513.0  15B 2-chloro-N-(trans-3-(3-chloro- 4-methylphenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

527.0  16B 2-chloro-N-(trans-3-(3,4- difluorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

515.0  17B 2-chloro-N-(trans-3-(4- chloro-3-fluorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

530.9  18B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(4- fluoro-2-methylphenyl)piperidin-4- yl)benzamide

511.0  19B 2-chloro-N-(trans-3-(4- chloro-3-methylphenyl)-1- (3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

527.0  20B 2-chloro-N-((3S,4S)-3-(4- chloro-3-methylphenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

527.0  21B 2-chloro-N-(cis-3-(4- chlorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin-4- yl)benzamide

513.0  22B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (difluoromethoxy)benzamide

537.1  23B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-5- carboxamide

489.0  24B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2- (morpholin-4-yl)ethoxy) nicotinamide

601.1  25B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2- (dimethylamino)ethoxy) nicotinamide

559.1  26B N-((3S,4R)-3-phenyl-1- (quinazolin-6-ylcarbonyl)piperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

506.1  27B N-((3S,4R)-1-((1-methyl-1H- imidazo[4,5-b]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

509.2  28B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

557.1  29B N-((3S,4R)-1-((2-hydroxy-4- methyl-1,3-thiazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

506.1  30B ethyl 1-methyl-5-(((3S,4R)-3- phenyl-4-((2-(trifluoromethoxy)benzoyl)amino)piperidin-1-yl) carbonyl)-1H-pyrazole-3- carboxylate

545.1  31B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (difluoromethoxy)pyridine-2- carboxamide

538.1  32B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6- methoxypyridine-2- carboxamide

502.1  33B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- methylpyridine-2-carboxamide

486.1  34B N-((3S,4R)-1-((1- (isopropylsulfonyl)-4-methyl-1H-pyrrol-3-yl)carbonyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

578.1  35B N-((3S,4R)-1-((5- ((cyclopropylcarbonyl)amino)-3-methyl-2-thienyl)carbonyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

572.1  36B N-((3S,4R)-1-((2-acetamido-4- methyl-1,3-thiazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

547.0  37B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(3- (morpholin-4-yl)propoxy)-4-(trifluoromethyl)nicotinamide

683.2  38B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2- (dimethylamino)ethoxy)-4-(trifluoromethyl)nicotinamide

627.0  39B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2- (morpholin-4-yl)ethoxy)-4-(trifluoromethyl)nicotinamide

669.2  40B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(3- (dimethylamino)propoxy)-4-(trifluoromethyl)nicotinamide

641.1  41B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(3H- [1,2,3]triazolo(4,5-b]pyridin-3-yloxy)-4-(trifluoromethyl) nicotinamide

672.3  42B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-oxo- 1,6-dihydropyridine-2- carboxamide

488.0  43B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- methoxy-1-methyl-1H-pyrazole- 5-carboxamide

505.1  44B N-((3S,4R)-1-((5,6- dimethoxypyridin-2-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

515.1  45B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

536.1  46B N-((3S,4R)-1-((5-cyano-6- methoxy-2-methylpyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

524.2  47B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2- hydroxyethoxy)-4-(trifluoromethyl)nicotinamide

600.0  48B dibenzyl 2-((5-(((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)carbamoyl)-4-(trifluoromethyl) pyridin-2-yl)oxy) ethyl phosphate

860.1  49B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

522.1  50B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

542.0  51B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

560.0  52B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

545.1  53B N-((3S,4R)-1-((2-amino-4- methyl-1,3-thiazol-5-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

508.1  54B N-((3S,4R)-1-((2-acetamido-4- methyl-1,3-thiazol-5-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

550.1  55B N-(cis-1′-(3,4- dimethoxybenzoyl)-1,3′- bipiperidin-4′-yl)-2-(trifluoromethoxy)benzamide

536.1  56B N-((3S,4R)-1-((5,6-dimethoxy-1-oxidopyridin-3-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

531.1  57B N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

521.0  58B N-((3S,4R)-1- ((8-chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

507.2  59B 5-chloro-N-((3S,4R)-1- ((8-chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

541.2  60B 5-chloro-N-((3S,4R)-1- ((8-chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- carboxamide

595.0  61B N-((3S,4R)-1-((8- cyclopropylquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

564.1  62B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- isopropyl-3-methyl-1H-pyrazole- 5-carboxamide

517.1  63B N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

506.1  64B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

515.1  65B N-((3S,4R)-1-((8-chloroimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

543.0  66B N-((3S,4R)-1-(3- (difluoromethyl)-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

549.1  67B N-((3S,4R)-1-(3-cyclopropyl-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

539.1  68B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- cyclopropylpyridine-2- carboxamide

512.1  69B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methyl-2-oxo-2,3-dihydro-1,3-oxazole-4-carboxamide

492.1  70B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

530.2  71B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3,4- trimethyl-1H-pyrazole-5- carboxamide

503.1  72B N-((3S,4R)-1-((3-methoxy-1- methyl-1H-pyrazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

488.1  73B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxamide

541.1  74B N-((3S,4R)-1-((8- methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

520.2  75B N-((3S,4R)-1-((3-methoxy-1- methyl-1H-pyrazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

491.1  76B N-((3S,4R)-1-((4-acetyl-3,5- dimethyl-1H-pyrrol-2-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

514.1  77B N-((3S,4R)-1-((4-acetyl-3,5- dimethyl-1H-pyrrol-2-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

513.0  78B 4-chloro-N-((3S,4R)-1-((5- chloro-6-methoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethyl) benzamide

552.1  79B N-((3S,4R)-1-(imidazo[1,2-a] pyridin-6-ylcarbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

509.2  80B N-((3S,4R)-1-(imidazo[1,2-a] pyridin-2-ylcarbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

509.2  81B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

543.3  82B N-((3S,4R)-1-((5- methoxypyridin-2-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

500.1  83B N-((3S,4R)-1-((5,6- dicyanopyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

520.1  84B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

543.2  85B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperdin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

558.2  86B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

561.2  87B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

608.2  88B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

611.1  89B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

543.2  90B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

558.2  91B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

561.2  92B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

608.2  93B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

611.1  94B N-((3S,4R)-1- ((8-chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-4- (trifluoromethyl)nicotinamide

682.3  95B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

523.2  96B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

561.1  97B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4- yl)benzamide

480.2  98B N-((3S,4R)-1-(3,4- dichlorobenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

537.1  99B N-((3S,4R)-1-(3-chloro-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

533.1 100B N-((3S,4R)-1-(4- methoxybenzoyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

499.1 101B N-((3S,4R)-3-phenyl-1- (pyridazin-4-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

471.1 102B N-((3S,4R)-1-(3-chloro-4- (methylsulfonyl)benzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

581.1 103B N-((3S,4R)-1-(1,3-benzothiazol- 6-ylcarbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

526.2 104B N-((3S,4R)-1-((1-methyl-1H- benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

523.2 105B N-((3S,4R)-1-(3,4- diethoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

557.3 106B N-((3S,4R)-1-(2-naphthoyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

519.2 107B N-((3S,4R)-3-phenyl-1- (quinolin-6-ylcarbonyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

520.2 108B N-((3S,4R)-1-(2-chloro-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

533.1 109B N-((3S,4R)-1-(2-fluoro-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

517.2 110B N-((3S,4R)-3-phenyl-1-(4- (trifluoromethoxy)benzoyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

553.1 111B N-((3S,4R)-1-(4-methoxy-3,5- dimethylbenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

527.2 112B N-((3S,4R)-1-((5-chloro-6- methoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

534.2 113B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(4-methoxyphenyl)piperidin-4- yl)benzamide

509.2 114B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(4-fluorophenyl)piperidin-4- yl)benzamide

497.1 115B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(4-fluoro-3-methylphenyl) piperidin-4-yl)benzamide

511.1 116B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(4-fluoro-2-methylphenyl) piperidin-4-yl)benzamide

511.1 117B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(pyridin-3-yl)piperidin-4- yl)benzamide

480.2 118B 3-chloro-N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)pyridine-2- carboxamide

472.1 119B 2-chloro-N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)nicotinamide

472.1 120B 3-chloro-N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)pyrazine-2- carboxamide

473.0 121B N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)-4- (trifluoromethyl)nicotinamide

506.1 122B N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethyl)nicotinamide

506.1 123B 2-(methylsulfonyl)-N-((3S,4R)- 3-phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl) benzamide

515.0 124B 2-cyano-N-((3S,4R)-3-phenyl-1- (quinoxalin-6-ylcarbonyl)piperidin-4-yl)benzamide

462.0 125B 1-isopropyl-N-((3S,4R)-3- phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H- pyrazole-5-carboxamide

469.1 126B 1-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H-pyrazole-5- carboxamide

441.1 127B 1-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H-imidazole-5- carboxamide

441.0 128B 1-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H-imidazole-2- carboxamide

441.0 129B 5-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1,3-thiazole-4- carboxamide

458.0 130B 5-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1,3-oxazole-4- carboxamide

442.1 131B 5-methyl-2-oxo-N-((3S,4R)-3- phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-2,3- dihydro-1,3-oxazole-4- carboxamide

458.0 132B 5-chloro-1-methyl-N-((3S,4R)- 3-phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H- pyrazole-4-carboxamide

475.1 133B 1,3-dimethyl-N-((3S,4R)-3- phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H- pyrazole-5-carboxamide

455.1 134B 1,3-dimethyl-N-((3S,4R)-3- phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1H- pyrazole-4-carboxamide

455.1 135B 5-methyl-N-((3S,4R)-3-phenyl- 1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl)-1,2-oxazole-4- carboxamide

442.1 136B 3-chloro-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)pyridine- 2-carboxamide

481.0 137B 2-chloro-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl) nicotinamide

481.1 138B 3-chloro-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl) pyrazine-2-carboxamide

481.9 139B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-4- (trifluoromethyl)nicotinamide

515.1 140B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethyl)nicotinamide

515.1 141B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (methylsulfonyl)benzamide

524.2 142B 2-cyano-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl) benzamide

471.1 143B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- isopropyl-1H-pyrazole-5- carboxamide

478.1 144B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-5- carboxamide

449.9 145B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-imidazole-5- carboxamide

450.0 146B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-imidazole-2- carboxamide

450.0 147B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methyl-1,3-thiazole-4- carboxamide

467.0 148B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methyl-1,3-oxazole-4- carboxamide

451.0 149B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methyl-2-oxo-2,3-dihydro-1,3-oxazole-4-carboxamide

467.1 150B 5-chloro-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-4- carboxamide

484.1 151B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-5- carboxamide

464.1 152B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-4- carboxamide

464.1 153B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methyl-1,2-oxazole-4- carboxamide

451.0 154B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

540.2 155B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-2-(difluoromethoxy)benzamide

605.2 156B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

540.2 157B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-2-(difluoromethoxy)benzamide

603.2 158B 6-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl) nicotinamide

506.0 159B 5-bromo-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl) pyridine-2-carboxamide

550.0 160B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,4- dimethyl-1H-pyrazole-5- carboxamide

489.0 161B 4-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

575.1 162B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,5- dimethyl-1H-pyrazole-4- carboxamide

489.0 163B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- methoxy-1-methyl-1H-pyrazole- 4-carboxamide

505.1 164B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- cyclopropyl-1-methyl-1H-pyrazole-4-carboxamide

515.1 165B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- ethoxy-1-methyl-1H-pyrazole-4- carboxamide

519.1 166B 5-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-4- carboxamide

523.0 167B 5-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

577.0 168B 1-tert-butyl-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxamide

585.1 169B 1-tert-butyl-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-5-cyclopropyl-1H-pyrazole-4- carboxamide

557.2 170B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- ethoxy-1-methyl-1H-pyrazole-5- carboxamide

519.1 171B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-(2- methoxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide

549.1 172B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- cyclopropyl-methyl-1H- pyrazole-5-carboxamide

515.1 173B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- isopropyl-1-methyl-1H-pyrazole- 5-carboxamide

517.1 174B 3-tert-butyl-N-((3S,4R)-1-((8-chloroquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5- carboxamide

531.1 175B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- methoxy-1-methyl-1H-pyrazole- 4-carboxamide

505.1 176B 3-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide

587.0 177B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

543.1 178B 3-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-5-(methylsulfanyl)-1H-pyrazole-4-carboxamide

555.0 179B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxamide

541.1 180B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- (difluoromethoxy)-1-methyl-1H-pyrazole-4-carboxamide

541.1 181B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- (difluoromethyl)-1H-pyrazole-4- carboxamide

511.0 182B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- cyclopropyl-1H-pyrazole-4- carboxamide

501.1 183B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- cyclopropyl-1-methyl-1H-pyrazole-4-carboxamide

515.1 184B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-(2,2- difluoroethyl)-3-methyl-1H-pyrazole-5-carboxamide

539.0 185B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- (difluoromethyl)-5-methyl-1H-pyrazole-3-carboxamide

525.1 186B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

543.1 187B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- isopropyl-1H-pyrazole-4- carboxamide

503.1 188B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-4- carboxamide

475.1 189B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-4- carboxamide

489.0 190B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3,5- trimethyl-1H-pyrazole-4- carboxamide

503.1 191B N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

533.1 192B N-((3S,4R)-3-phenyl-1-(1H- pyrazolo[3,4-b]pyridin-5-ylcarbonyl)piperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

495.0 193B N-((3S,4R)-1-((1-methyl-1H- benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

508.1 194B N-((3S,4R)-1-((3-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

509.3 195B N-((3S,4R)-1-((5-chloro-6- (2,2,2-trifluoroethoxy)pyridin-3-yl)carbonyl)-3-phenylpiperidin- 4-yl)-2-(trifluoromethoxy) benzamide

602.0 196B N-((3S,4R)-1-((5-chloro-6-(2,2- difluoroethoxy)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

584.0 197B N-((3S,4R)-1-((5-chloro-6- ((²H₃)methyloxy)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

537.1 198B N-((3S,4R)-1-((5-bromo-6- chloropyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

582.0 199B N-((3S,4R)-1-((5-bromo-6- methoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

578.0 200B N-((3S,4R)-1-((5-bromo-6- ((²H₃)methyloxy)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

581.0 201B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (difluoromethoxy)benzamide

537.2 202B N-((3R,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-2-(difluoromethoxy) benzamide

555.2 203B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (difluoromethoxy)benzamide

537.2 204B N-((3S,4S)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4- yl)-2-(difluoromethoxy) benzamide

555.1 205B 2-chloro-N-((3S,4R)-1-((5- chloro-6-methoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)benzamide

484.1 206B 2-chloro-N-((3S,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl) benzamide

480.1 207B N-((3S,4R)-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

529.1 208B N-((3S,4R)-1-((2-methyl-2H- indazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

523.1 209B N-((3S,4R)-1-(1H-indazol-5- ylcarbonyl)-3-phenylpiperidin-4-yl)-2-(trifluoromethoxy) benzamide

509.1 210B N-((3S,4R)-3-phenyl-1-(1H- pyrrolo[2,3-b]pyridin-5-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

509.1 213B N-((3S,4R)-1-((2-methyl-7-oxo-4,7-dihydro[1,2,4]triazolo[1,5-a] pyrimidin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

541.2 214B N-((3S,4R)-1-((2-oxo-2,3- dihydro-1H-benzimidazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

525.1 216B N-((3S,4R)-3-phenyl-1-(1H- pyrazolo[3,4-b]pyridin-5-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

510.1 217B N-((3S,4R)-1-(1H-benzotriazol-5-ylcarbonyl)-3-phenylpiperidin- 4-yl)-2-(trifluoromethoxy) benzamide

510.0 218B N-((3S,4R)-1-((2-methyl-2H- indazol-5-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

523.1 219B N-((3S,4R)-1-(4-methoxy-2,5- dimethylbenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

527.1 221B N-((3S,4R)-1-((8- methoxyquinolin-5-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

550.1 222B N-((3S,4R)-1-(3-chloro-4- ethoxy-5-fluorobenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

565.1 223B N-((3S,4R)-1-((3-bromo-8- methylquinolin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

612.0 224B N-((3S,4R)-1-(3-cyano-4- fluorobenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

512.0 225B N-((3S,4R)-1-((6- chloroimidazo[1,2-b]pyridazin-2-yl)carbonyl)-3- phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

544.0 226B N-((3S,4R)-3-phenyl-1-(thieno [2,3-c]pyridin-2-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

526.1 227B N-((3S,4R)-1-((6-chloroimidazo[1,2-a]pyrimidin-2-yl)carbonyl)- 3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

542.1 228B N-((3S,4R)-1-((5-methoxy-1- benzothiophen-2-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

555.0 229B N-((3S,4R)-3-phenyl-1-(1H- pyrrolo[3,2-b]pyridin-2-ylcarbonyl)piperidin-4-yl)-2- (trifluoromethoxy)benzamide

509.1 230B N-((3S,4R)-1-((5-methoxy-1H- pyrrolo[2,3-c]pyridin-2-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

539.1 231B N-((3S,4R)-1-((1-methyl-1H- benzimidazol-5-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

523.1 232B N-((3S,4R)-1-(1,3-benzothiazol- 5-ylcarbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

526.1 233B N-((3S,4R)-1-((4-chloro-1H- pyrrolo[2,3-b]pyridin-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

543.0 234B N-((3S,4R)-1-((5-fluoro-1- benzofuran-2-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

527.0 235B N-((3S,4R)-1-((5-acetyl-2- thienyl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

517.0 236B N-((3S,4R)-1-(3-fluoro-4- methoxybenzoyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

517.1 237B N-((3S,4R)-1-((3-methoxy-1,2- oxazol-5-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

489.9 238B N-((3S,4R)-1-((3-oxo-2,3- dihydro-1,2-oxazol-5-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

476.0 239B methyl 5-(((3S,4R)-3-phenyl-4- ((2-(trifluoromethoxy)benzoyl)amino)piperidin-1-yl)carbonyl) pyridine-2-carboxylate

528.0 240B N-((3S,4R)-1-((2-amino-1,3- benzoxazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

525.1 241B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

540.1 242B 6-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-4- (trifluoromethyl)nicotinamide

574.0 243B 5-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-4- carboxamide

509.1 244B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(pyridin-4-yl)piperidin-4-yl)benzamide

480.0 245B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-(trifluoromethyl)pyridine-2-carboxamide

558.2 246B 3-chloro-N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)pyridine- 2-carboxamide

506.0 247B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(1H- pyrazol-yl)-4-(trifluoromethyl)nicotinamide

606.1 248B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6-(2,2,2- trifluoroethoxy)-4-(trifluoromethyl)nicotinamide

638.1 249B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl-6-(2,2- difluoroethoxy)-4-(trifluoromethyl)nicotinamide

619.9 250B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-6- methoxy-4-(trifluoromethyl) nicotinamide

570.1 251B N-((3S,4R)-1-((5,6- dichloropyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

538.1 252B N-((3S,4R)-1-((5-bromopyridin-2-yl)carbonyl)-3-phenylpiperidin- 4-yl)-2-(trifluoromethoxy) benzamide

548.0 253B N-(trans-1′-((5,6- dimethoxypyridin-3-yl)carbonyl)-1,3′-bipiperidin-4′-yl)-2- (trifluoromethoxy)benzamide

537.1 254B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

555.0 255B N-((3S,4R)-1-((5-cyano-6- methoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

525.1 256B N-((3S,4R)-1-((5-cyano-6- ((²H₃)methyloxy)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)- 2-(trifluoromethoxy)benzamide

528.1 257B N-((3S,4R)-1-((5,6-bis((²H₃)methyloxy)pyridin-3-yl)carbonyl)- 3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

536.2 258B N-((3S,4R)-1-((6-((²H₃) methyloxy)(5-²H)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)- 2-(trifluoromethoxy)benzamide

504.1 259B N-((3S,4R)-1-((5-chloro-6-(1H- pyrazol-1-yl)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4- yl)-2-(trifluoromethoxy) benzamide

570.0 260B N-((3S,4R)-1-((5-chloro-6-oxo-1,6-dihydropyridin-3-yl)carbonyl)- 3-phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

520.0 261B N-((3S,4R)-1-((6-amino-5- chloropyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-2- (trifluoromethoxy)benzamide

519.1 262B N-((3S,4R)-1-((5-bromo-6- (dimethylamino)pyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)- 2-(trifluoromethoxy)benzamide

591.0 263B 2-(difluoromethoxy)-N-((3S,4R)- 3-phenyl-1-(quinoxalin-6-ylcarbonyl)piperidin-4-yl) benzamide

503.1 264B 2-(difluoromethoxy)-N-((3S,4R)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-phenylpiperidin-4-yl)benzamide

512.1 265B N-((3S,4R)-1-((6-(bis (cyclopropylcarbonyl)amino)-5-chloropyridin-3-yl)carbonyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

653.3 266B N-((3S,4R)-1-((5-chloro-6- ((cyclopropylcarbonyl)amino)pyridin-3-yl)carbonyl)-3- phenylpiperidin-4-yl)-2-(trifluoromethoxy)benzamide

587.0 267B N-((3S,4R)-1-((8-chloro[1,2,4] triazolo[4,3-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)- 2-(trifluoromethoxy)benzamide

544.0 268B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(pyridin-4-yl)piperidin-4-yl)benzamide

480.0 269B 2-chloro-N-(cis-3-(3-chloro- 4-fluorophenyl)-1-(3,4-dimethoxybenzoyl)piperidin- 4-yl)benzamide

531.0 270B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(3-methyl-2-thienyl)piperidin-4- yl)benzamide

499.0 271B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-3- yl)piperidin-4-yl)benzamide

483.1 272B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-4- yl)piperidin-4-yl)benzamide

483.2 273B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-5- yl)piperidin-4-yl)benzamide

483.2 274B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-4- yl)piperidin-4-yl)benzamide

483.2 275B 2-chloro-N-(trans-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-5- yl)piperidin-4-yl)benzamide

483.2 276B N-(trans-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(1H-pyrazol-1- yl)piperidin-4-yl)-2-(trifluoromethoxy)benzamide

520.1 277B 2-chloro-N-(cis-1-(3,4- dimethoxybenzoyl)-3-(1-methyl-1H-pyrazol-3-yl) piperidin-4-yl)benzamide

483.0 278B N-(trans-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(1H-1,2,3-triazol-1-yl) piperidin-4-yl)-2- (trifluoromethoxy)benzamide

521.0 279B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

522.2 280B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

552.2 281B 3-cyclopropyl-N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)pyridine-2-carboxamide

492.3 282B 3-cyclopropyl-N-((3S,4R)-1-((8-methoxyquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)pyridine-2-carboxamide

508.2 283B 3-cyclopropyl-N-((3S,4R)-1- ((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin- 4-yl)pyridine-2-carboxamide

494.2 284B 3-cyclopropyl-N-((3S,4R)-1-((2- methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

524.3 285B 3-(difluoromethoxy)-N-((3S,4R)- 1-((8-methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)pyridine-2-carboxamide

534.2 286B 3-(difluoromethoxy)-N-((3S,4R)-1-((3,8-dimethylimidazo[1,2-a] pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)pyridine-2- carboxamide

520.2 287B 3-(difluoromethoxy)-N-((3S,4R)- 1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

520.2 288B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)pyridine-2-carboxamide

540.2 289B 3-(difluoromethoxy)-N-((3S,4R)-1-((2-methoxy-1,4-dimethyl-1H- benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)pyridine-2- carboxamide

550.2 290B 3-(difluoromethoxy)-N-((3S,4R)- 1-((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)pyridine-2-carboxamide

518.2 291B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-5- carboxamide

485.2 292B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

471.3 293B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)- 1,3-dimethyl-1H-pyrazole-5-carboxamide

491.2 294B 1,3-dimethyl-N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-1H-pyrazole-5-carboxamide

469.2 295B 1-(2,2-difluoroethyl)-N-((3S,4R)- 1-((2-methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-3-methyl-1H-pyrazole-5- carboxamide

551.2 296B 1-(2,2-difluoroethyl)-3-methyl- N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-1H-pyrazole-5-carboxamide

519.1 297B 1-(2,2-difluoroethyl)-N-((3S,4R)-1-((8-methoxyquinoxalin-6-yl) carbonyl)-3-phenylpiperidin-4-yl)-3-methyl-1H-pyrazole-5- carboxamide

535.2 298B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

555.2 299B 1-methyl-N-((3S,4R)-1-((8- methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)-1H-pyrazole-5- carboxamide

523.2 300B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

545.1 301B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

525.2 302B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 5-carboxamide

525.2 303B 3-ethoxy-1-methyl-N-((3S,4R)- 1-((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1H-pyrazole-5-carboxamide

499.2 304B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

521.2 305B 3-ethoxy-N-((3S,4R)-1-((2- methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

531.2 306B 3-ethoxy-N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-5- carboxamide

515.2 307B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-ethoxy-1-methyl-1H-pyrazole-5- carboxamide

501.3 308B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-methoxy-1-methyl-1H-pyrazole-5- carboxamide

487.1 309B 3-methoxy-1-methyl-N-((3S,4R)- 1-((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1H-pyrazole-5-carboxamide

485.2 310B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

507.2 311B 3-methoxy-N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-1H-pyrazole-5- carboxamide

501.2 312B 3-(difluoromethoxy)-1-methyl-N-((3S,4R)-1-((8-methylquinoxalin- 6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1H- pyrazole-5-carboxamide

521.2 313B 3-(difluoromethoxy)-N-(3S,4R)- 1-((8-methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-1H-pyrazole-5- carboxamide

537.2 314B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5- carboxamide

543.2 315B 3-(difluoromethoxy)-N-((3S,4R)- 1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

523.2 316B 3-(difluoromethoxy)-N-((3S,4R)-1-((2-methoxy-1,4-dimethyl-1H- benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl- 1H-pyrazole-5-carboxamide

553.2 317B 3-(difluoromethoxy)-1,4- dimethyl-N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-1H-pyrazole-5-carboxamide

535.2 318B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)-1,4-dimethyl-1H-pyrazole-5- carboxamide

557.2 319B 3-(difluoromethoxy)-N-((3S,4R)-1-((3,8-dimethylimidazo[1,2-a] pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,4- dimethyl-1H-pyrazole-5- carboxamide

537.2 320B 3-(difluoromethoxy)-N-((3S,4R)- 1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,4-dimethyl-1H-pyrazole-5- carboxamide

537.2 321B 3-(difluoromethoxy)-N-((3S,4R)- 1-((8-methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,4-dimethyl-1H-pyrazole-5-carboxamide

551.2 322B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

485.3 323B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3,4-trimethyl-1H-pyrazole-5- carboxamide

485.3 324B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3,4- trimethyl-1H-pyrazole-5- carboxamide

499.2 325B 1,3,4-trimethyl-N-((3S,4R)-1- ((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1H-pyrazole-5-carboxamide

483.2 326B 3-cyclopropyl-N-((3S,4R)-1- ((2-methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

527.2 327B 3-cyclopropyl-methyl-N- ((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin- 4-yl)-1H-pyrazole-5- carboxamide

495.2 328B 3-cyclopropyl-N-((3S,4R)-1- ((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin- 4-yl)-1-methyl-1H-pyrazole-5-carboxamide

497.2 329B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-y)carbonyl)-3-phenylpiperidin-4- yl)-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxamide

517.2 330B 3-cyclopropyl-N-((3S,4R)-1- ((8-methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-1H-pyrazole-5- carboxamide

511.2 331B 3-cyclopropyl-N-((3S,4R)-1- ((3,8-dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

497.2 332B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

559.2 333B N-((3S,4R)-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

539.2 334B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

553.2 335B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

569.2 336B 5-chloro-N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

573.2 337B 5-chloro-N-((3S,4R)-1-((2- methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

589.3 338B 5-chloro-N-((3S,4R)-1-((8- chloro-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

579.1 339B 5-chloro-N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4- carboxamide

559.2 340B 5-chloro-1-methyl-N-((3S,4R)- 1-((8-methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

557.2 341B 5-chloro-1,3-dimethyl-N- ((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin- 4-yl)-1H-pyrazole-4- carboxamide

503.2 342B 5-chloro-N-((3S,4R)-1-((8- chloro-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4- carboxamide

525.2 343B 5-chloro-N-((3S,4R)-1-((2- methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4- carboxamide

535.2 344B 5-chloro-N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

505.2 345B 5-chloro-N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-1H-pyrazole-4- carboxamide

519.1 346B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

539.2 347B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

545.1 348B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)- 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

555.2 349B 1-methyl-N-((3S,4R)-1-((8- methylquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-5- (trifluoromethyl)-1H-pyrazole-4- carboxamide

523.2 350B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

525.2 351B N-((3S,4R)-3-(4-fluorophenyl)- 1-((2-methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

573.2 352B N-((3S,4R)-3-(4-fluorophenyl)- 1-((8-methoxyquinoxalin-6-yl)carbonyl)piperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

557.2 353B N-((3S,4R)-3-(4-fluorophenyl)- 1-((4-methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

559.2 354B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-(difluoromethoxy)pyridine-2-carboxamide

556.2 355B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

537.1 356B 2-(difluoromethoxy)-N-((3S,4S)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-(4-(trifluoromethyl)phenyl)piperidin-4-yl)benzamide

580.1 357B 2-(difluoromethoxy)-N-((3R,4R)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-phenylpiperidin-4-yl)benzamide

512.2 358B 2-(difluoromethoxy)-N-((3S,4S)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)benzamide

530.2 359B N-((3S,4S)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

583.2 360B 2-(difluoromethoxy)-N-((3R,4R)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-(4-(trifluoromethyl)phenyl)piperidin-4-yl)benzamide

580.1 361B 2-(difluoromethoxy)-N-((3R,4R)-1-((5,6-dimethoxypyridin-3-yl) carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)benzamide

530.2 362B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-3-(trifluoromethyl)pyridine-2- carboxamide

583.2 363B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-(difluoromethoxy)-1,4-dimethyl-1H-pyrazole-5- carboxamide

573.2 364B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-cyclopropylpyridine-2- carboxamide

530.1 365B 2-(difluoromethoxy)-N-((3S,4S)- 1-((5,6-dimethoxypyridn-3-yl)carbonyl)-3-phenylpiperidin-4- yl)benzamide

512.2 366B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

538.2 367B 3-cyclopropyl-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

510.2 368B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-cyclopropylpyridine-2-carboxamide

514.1 369B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

501.3 370B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-5- carboxamide

471.3 371B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

487.2 372B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

491.2 373B 1-(2,2-difluoroethyl)-N-((3S,4R)-1-((3,8-dimethylimidazo[1,2-a] pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-methyl- 1H-pyrazole-5-carboxamide

521.2 374B 1-(2,2-difluoroethyl)-N-((3S,4R)- 1-((4-methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-methyl-1H-pyrazole-5-carboxamide

537.2 375B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5- carboxamide

541.3 376B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

541.3 377B 3-ethoxy-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

517.2 378B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

521.2 379B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-ethoxy-1-methyl-1H-pyrazole-5-carboxamide

501.3 380B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

507.2 381B 3-methoxy-N-((3S,4R)-1-((2- methoxy-1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

517.2 382B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-methoxy-1-methyl-1H-pyrazole-5-carboxamide

487.2 383B 3-methoxy-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

503.2 384B 3-(difluoromethoxy)-N-((3S,4R)- 1-((4-methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

539.2 385B 3-(difluoromethoxy)-N-((3S,4R)-1-((3,8-dimethylimidazo[1,2-a] pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1-methyl- 1H-pyrazole-5-carboxamide

523.2 386B 3-(difluoromethoxy)-N-((3S,4R)-1-((2-methoxy-1,4-dimethyl-1H- benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,4- dimethyl-1H-pyrazole-5- carboxamide

567.3 387B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)-1,4-dimethyl-1H-pyrazole-5- carboxamide

557.2 388B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

505.2 389B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

501.3 390B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

515.2 391B 1,3-dimethyl-N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

537.2 392B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

559.2 393B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

555.2 394B 5-chloro-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

575.2 395B 5-chloro-N-((3S,4R)-1-((4- chloro-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4- carboxamide

525.2 396B 5-chloro-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4- carboxamide

521.2 397B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

541.3 398B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

545.1 399B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-trifluorophenyl)piperidin-4-yl)- 3-(trifluoromethyl)pyridine-2-carboxamide

533.2 400B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

536.2 401B N-((3S,4S)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

515.2 402B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

536.2 403B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

586.1 404B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-3- (trifluoromethyl)pyridine-2- carboxamide

515.2 405B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 5-(difluoromethoxy)-1,4-dimethyl-1H-pyrazole-3- carboxamide

573.2 406B N-((3S,4S)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 3-(trifluoromethyl)pyridine-2-carboxamide

533.2 407B N-((3S,4S)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

518.2 408B N-((3S,4S)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-(4-(trifluoromethyl)phenyl) piperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

586.1 409B N-((3R,4R)-1-((5,6- dimethoxypyridin-3-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

518.2 410B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 1,3,4-trimethyl-1H-pyrazole-5-carboxamide

521.2 411B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide

585.1 412B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1- methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

539.2 413B 3-cyclopropyl-N-((3S,4R)-1- ((3,8-dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2- carboxamide

494.2 414B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-cyclopropylpyridine-2- carboxamide

514.1 415B 3-(difluoromethoxy)-N-((3S,4R)- 1-((4-methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

536.2 416B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)pyridine-2-carboxamide

540.2 417B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-(2,2-difluoroethyl)-3-methyl-1H-pyrazole-5- carboxamide

541.3 418B 1-(2,2-difluoroethyl)-N-((3S,4R)- 1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-3-methyl-1H-pyrazole-5-carboxamide

521.2 419B 3-(difluoromethoxy)-N-((3S,4R)- 1-((4-methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,4-dimethyl-1H-pyrazole-5- carboxamide

553.2 420B 3-cyclopropyl-N-((3S,4R)-1-((4- methoxy-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

513.2 421B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-4-(trifluoromethyl)-1H- pyrazole-5-carboxamide

539.2 422B 5-chloro-N-((3S,4R)-1-((1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

505.2 423B 1,3-dimethyl-N-((3S,4R)-1-((8-methylquinoxalin-6-yl)carbonyl)- 3-phenylpiperidin-4-yl)-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

547.2 424B N-((3S,4R)-1-((2-methoxy-1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

579.2 425B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

549.2 426B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

569.1 427B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,3- dimethyl-5-(methylsulfonyl)-1H-pyrazole-4-carboxamide

563.2 428B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

525.2 429B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

542.2 430B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5- carboxamide

543.2 431B N-((3S,4R)-1-((4-chloro-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

505.2 432B 5-chloro-N-((3S,4R)-1-((4- chloro-1-methyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

579.0 433B 5-chloro-N-((3S,4R)-1-((1,4- dimethyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide

559.2 434B N-((3S,4R)-1-((8-chloro-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

569.1 435B N-((3S,4R)-1-((1,4-dimethyl-1H-benzimidazol-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-5-(methylsulfonyl)-1H- pyrazole-4-carboxamide

549.2 436B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

555.2 437B N-((3S,4R)-1-((3,8- dimethylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

539.3 438B N-((3S,4R)-1-((4-methoxy-1- methyl-1H-benzimidazol-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole-5- carboxamide

555.2 439B N-((3S,4R)-1-((8- methoxyquinoxalin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-1,4- dimethyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

553.2 440B N-(cis-3-cyclopropyl-1- (3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

493.2 441B N-(cis-3-cyclohexyl-1- (3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

535.2 442B N-(trans-3-cyclohexyl-1- (3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

535.2 443B N-(tras-3-cyclopentyl-1- (3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

521.2 444B N-(cis-3-cyclopentyl-1- (3,4-dimethoxybenzoyl)piperidin-4-yl)-2-(trifluoromethoxy) benzamide

521.2 445B 3-cyclopropyl-N-((3S,4R)-1- ((8-methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

513.2 446B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-3-(trifluoromethyl)pyridine-2-carboxamide

538.2 447B 3-ethoxy-N-((3S,4R)-1-((8- methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

517.2 448B 3-cyclopropyl-N-((3S,4R)-1- ((8-methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

510.3 449B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3,4-trimethyl-1H-pyrazole-5-carboxamide

501.3 450B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide

555.2 451B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

541.3 452B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

541.3 453B 1-(2,2-difluoroethyl)-N-((3S,4R)-1-((8-methoxy-3-methylimidazo [1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4-yl)-3-methyl- 1H-pyrazole-5-carboxamide

537.2 454B 3-(difluoromethoxy)-N-((3S,4R)- 1-((8-methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,4-dimethyl-1H-pyrazole-5- carboxamide

553.2 455B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-1H-pyrazole-5-carboxamide

487.2 456B 3-methoxy-N-((3S,4R)-1-((8- methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

503.2 457B 5-chloro-N-((3S,4R)-1-((8- methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-carboxamide

575.2 458B 5-chloro-N-((3S,4R)-1-((8- methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)-1,3-dimethyl-1H-pyrazole-4- carboxamide

521.2 459B N-((3S,4R)-1-((8-methoxy-3- methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3-phenylpiperidin-4- yl)-1,3-dimethyl-5-(methylsulfonyl)-1H-pyrazole-4- carboxamide

565.3 460B 3-(difluoromethoxy)-N-((3S,4R)- 1-((8-methoxy-3-methylimidazo[1,2-a]pyridin-6-yl)carbonyl)-3- phenylpiperidin-4-yl)pyridine-2-carboxamide

536.3 461B 2-chloro-N-((3S,4S)-1-(3,4- dimethoxybenzoyl)-3-phenylpiperidin-4-yl)benzamide

479.1 462B N-((3S,4R)-1-((8- chloroquinoxalin-6-yl)carbonyl)-3-(4-fluorophenyl)piperidin-4-yl)- 1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

575.1

Formulation Example 1

Each medicament containing the compound of the present invention as anactive ingredient can be produced, for example, according to thefollowing recipe:

[Expression 1]

Capsule (1) Compound obtained in Example 1 40 mg (2) Lactose 70 mg (3)Microcrystalline cellulose 9 mg (4) Magnesium stearate 1 mg One capsule120 mg

The components (1), (2) and (3) and a ½ amount of the component (4) aremixed and then granulated. The remaining amount of the component (4) isadded thereto, and the whole is encapsulated in a gelatin capsule shell.

[Expression 2]

2. Tablet (1) Compound obtained in Example 1 40 mg (2) Lactose 58 mg (3)Corn starch 18 mg (4) Microcrystalline cellulose 3.5 mg (5) Magnesiumstearate 0.5 mg One tablet 120 mg

The components (1), (2) and (3), a ⅔ amount of the component (4) and a ½amount of the component (5) are mixed and then granulated. The remainingamounts of the components (4) and (5) are added to this granule, whichis then molded into a tablet by compression.

Formulation Example 2

50 mg of the compound obtained in Example 1 is dissolved in 50 mL ofJapanese Pharmacopoeia distilled water for injection, and then, theamount of the solution is adjusted to 100 mL by the addition of JapanesePharmacopoeia distilled water for injection. This solution is filteredunder sterile conditions. Next, vials for injection are filled with thissolution at 1 mL/vial under sterile conditions, freeze-dried, andhermetically sealed.

Test Example 1 SPT Enzyme Inhibition Test

Full-length human SPT1, human SPT2 and human ssSPTa used had amino acidsequences identical to NCBI Accession Nos. NM_006415, NM_004863 andNM_138288, respectively. pcDNA3.1 vectors having an insert of a sequenceof interest were prepared, and FreeStyle 293 cells (Life Technologies,Inc., Carlsbad, Calif., US) were cotransfected with the human SPT1,human SPT2, and human ssSPTa expression vectors according to theprotocol of FreeStyle 293 Expression system. After culture for 3 days,the cells were recovered and frozen at −80° C. to obtain expressingcells. The frozen cells were suspended in a 50 mM Hepes buffer (pH 7.5)containing 250 mM sucrose, 5 mM ethylenediaminetetraacetic acid (EDTA),5 mM dithiothreitol (DTT) and Complete, EDTA-free (Roche AppliedScience, Penzberg, Upper Bavaria, Germany). The cells were disrupted (onice, 20,000 rpm, 20 sec×2) using POLYTORON (Central Scientific Commerce,Inc.). After centrifugation at 2000 rpm (850×g) for 10 minutes, thesupernatant was recovered. Subsequently, the supernatant was centrifugedat 40,000 rpm (186,010×g) for 60 minutes, and the supernatant wasdiscarded. The pellets were suspended in a 50 mM Hepes buffer (pH 7.5)containing 5 mM EDTA, 5 mM DTT and Complete, EDTA-free, passed through a40-μm cell strainer and stored at −80° C. The resultant was used as aSPT2-expressing membrane fraction. The protein concentration wasdetermined using CBB Protein Assay with bovine serum albumin used asstandards.

5 μL of each test compound was mixed with 10 μL of the 100 μg/mLSPT2-expressing membrane fraction using an assay buffer (100 mM Hepes(pH 8.0) containing 2.5 mM EDTA, 5 mM DTT and 0.01% fatty acid-freebovine serum albumin), and the mixture was left standing at roomtemperature for 60 minutes. Subsequently, 5 μL of a substrate solutioncontaining 2 mM L-serine and 20 μM palmitoyl CoA was added thereto, andan enzyme reaction was carried out in a 384-well plate using 20 μL intotal of the reaction system. After reaction at room temperature for 15minutes, the reaction was terminated by the addition of 20 μL of a 2%aqueous formic acid solution. Subsequently, 40 μL of acetonitrilecontaining 600 nM C17-sphinganine (Avanti Polar Lipids, Inc., Alabaster,Ala., US) was added thereto as an internal standard. The reaction samplewas subjected to on-line solid-layer extraction using RapidFire 300(Agilent Technologies Inc., Santa Clara, Calif., US). The SRM transitionof 3-ketodihydrosphingosine (reaction product) and C17-sphinganine(internal standard) was set to 300.5/270.3 and 288.4/60.2, respectively,on a positive SRM mode using API-4000 (AB SCIEX, Framingham, Mass., US)equipped with ESI probes. Mass chromatograms were obtained using Analystsoftware (version 1.5.0, AB SCIEX). Their mass chromatogram areas wererespectively calculated, and the rate of inhibition (%) by the testcompound was calculated using an area ratio (the value of the reactionproduct was divided by the value of the internal standard).

The test results are shown in Table 3.

TABLE 3 Example No. Rate of inhibition (%) at 1 μM  1A 91  2A 98  3A 98 17A 84  30A 93  36A 101  64A 82  74A 99  80A 99  84A 98  85A 99  91A 94100A 97 103A 95 117A 84 126A 101 132A 102 133A 101 153A 101 155A 103162A 100 165A 101 170A 99 171A 101 172A 93 178A 101 186A 101 201A 100217A 102  2B 99  3B 98  23B 101  25B 100  31B 102  35B 101  38B 101  44B98  55B 95  57B 96  58B 101  59B 101  64B 100  70B 100  72B 94  74B 100 81B 100  96B 102 102B 100 104B 101 114B 99 132B 98 139B 100 140B 101141B 101 144B 98 150B 101 151B 99 152B 96 166B 101 170B 100 191B 100241B 101 245B 100 246B 101 253B 97 254B 99 270B 89 276B 82 279B 103 324B99 330B 102 342B 101 344B 103 345B 102 352B 102 361B 102 412B 102

These results demonstrated that the compound of the present inventionhas an inhibitory effect on SPT.

Test Example 2 HCC4006 Cell Growth Inhibition Test

A lung adenocarcinoma cell line HCC4006 (ATCC) was cultured using anRPMI-1640 medium (Wako Pure Chemical Industries, Ltd.) containing 10%fetal bovine serum and penicillin/streptomycin. 250 cells per well wereinoculated into 40 μL of a medium in a 384-well culture plate. On thenext day, 10 μL of each test compound was added to the cells. Afterculture for 5 days, the medium was discarded, and 30 μL of CellTiter-GloLuminescent Cell Viability Assay solution (Promega Corp., Fitchburg,Wis., US) was added to each well. Light emission signals were measuredusing EnVision (PerkinElmer, Inc., Waltham, Mass., US). The rate ofinhibition (%) by the test compound was calculated according to thefollowing expression:Rate of inhibition (%)=(1−(Count of the testcompound−Blank)/(Control−Blank))×100

In the above expression, a count under compound non-addition conditionswas indicated as a control, and a count under cell-free conditions wasindicated as a blank.

The test results are shown in Table 4.

TABLE 4 Example No. Rate of inhibition (%) at 1 μM  2A 36  3A 41  36A 47 74A 51  80A 44  84A 32  85A 39 100A 39 126A 45 132A 52 133A 50 153A 53155A 53 162A 56 165A 52 170A 50 171A 50 178A 53 186A 47 201A 40  2B 55 3B 44  23B 53  25B 53  31B 57  35B 40  38B 46  44B 47  57B 54  58B 49 59B 53 (Rate of inhibition at 0.3 μM)  64B 49  70B 56  74B 45  81B 54 96B 49 102B 46 104B 53 114B 56 132B 45 139B 52 140B 49 141B 52 150B 47151B 51 152B 33 166B 53 170B 50 191B 47 241B 54 245B 53 246B 55 254B 55279B 44 324B 49 330B 49 342B 51 344B 51 345B 48 352B 50 361B 45 412B 47

These results demonstrated that the compound of the present inventioninhibits the growth of lung adenocarcinoma cells.

Test Example 3 Antitumor Test Using PL-21 Cell

The compound of the present invention was evaluated for its antitumoreffect on human leukemia cell line PL-21 cancer-bearing mice by thefollowing method.

The human leukemia cell line PL-21 (JCRB) was transplanted to each6-week-old Icr-scid female mouse (CLEA Japan Inc.) by the subcutaneousinjection of 3.0×10⁶ cells. The tumor size of successfully engraftedtumor was measured 13 days after the transplantation. The tumor volumewas calculated according to the following expression:Tumor volume=Major axis×Minor axis×Minor axis×(½)

Individuals in which the volume of the engrafted tumor reached 100 to150 mm³ were selected and used in the experiment as groups eachinvolving 5 or 6 individuals. A 0.5% methylcellulose suspension of eachtest compound was orally administered to each mouse using the dose(indicated by single dose), the number of doses and the dosing periodshown in Table 5. The tumor sizes at the day before the start of theadministration and one day after the completion of the administrationwere measured and the tumor volume was calculated.

The rate of tumor growth (T/C (%)) in the test compound administrationgroup compared with a control administration group was calculatedaccording to the following expression:T/C (%)=(Tumor volume after the completion of the administration of thetest compound administration group−Tumor volume before the start of theadministration of the test compound administration group)/(Tumor volumeafter the completion of the administration of the control administrationgroup−Tumor volume before the start of the administration of the controladministration group)×100

The test results are shown in Table 5.

TABLE 5 Example T/C Dose No. (%) (mg/kg) The number of doses, dosingperiod 162A  52 10 Administered once every two days, 14 days 162A  38 30Administered once every two days, 14 days 81B 63 10 Administered onceevery two days, 14 days 81B 32 30 Administered once every two days, 14days 81B 16 10 Administered every day for 3 days, 4-day drug holiday, 2cycles

These results demonstrated that the compound of the present inventionhas an antitumor effect.

Test Example 4 Efficacy Evaluation Test Using Niemann-Pick Disease ModelCell

A normal line and an acidic sphingomyelinase-deficient cell line(Niemann-Pick disease model cells), which is responsible forNiemann-Pick disease, are each cultured using Iscove's ModifiedDulbecco's Medium containing 10% fetal bovine serum andpenicillin/streptomycin. At the day following the inoculation to theculture plate, the medium is replaced, and the cells are cultured in amedium containing each SPT inhibitor for 4 days. After the culture, themedium is discarded, and sphingolipids such as sphingomyelin in thecells are extracted with hexane and quantified by use of TLC, gaschromatography or the like.

Test Example 5 Efficacy Evaluation Test Using Niemann-Pick Disease ModelMouse

The Niemann-Pick disease-ameliorating effect of each SPT inhibitor isconfirmed using Niemann-Pick disease model mice (e.g., acidicsphingomyelinase-deficient mice (FASEB J. 2000; 14: 1988) or NPC miceconfirmed to have sphingomyelin accumulation (Nat Med. 2008; 14: 1247)).These model mice manifest symptoms similar to those of humanNiemann-Pick disease associated with sphingomyelin accumulation, etc.,in the liver, the lung or the like. Furthermore, these mice manifestliver damage and nerve dysfunction and die at the age of approximately12 weeks without treatment.

Four-week-old Niemann-Pick disease model mice are used. The test isstarted at the age of 4 weeks, and a 0.5% methyl cellulose suspension ofeach test compound is orally administered to the mice for 2 or 4 weeks.After the continuous administration, organ samples are collected. Theeffect of lowering liver damage markers serum AST (aspartateaminotransferase) and ALT (alanine aminotransferase) is tested as anevaluation parameter for the ameliorating effect of the SPT inhibitor.In addition, its ameliorating effect in each tissue image of the liver,central nerve and the like is also tested. In order to confirm SPTinhibitory activity, the effect of lowering sphingolipids such assphingomyelin in tissues is further tested.

INDUSTRIAL APPLICABILITY

The compound of the present invention can be used as a SPT inhibitor andcan be useful as a prophylactic or therapeutic agent for SPT-relateddiseases including cancer and the like.

The present application is based on Japanese Patent Application No.2015-086195 filed in Japan, the contents of which are incorporatedherein by their entirety.

The invention claimed is:
 1. A method for treating Niemann-Pick diseasein a mammal, comprising administering an effective amount of a compoundor a salt thereof to the mammal, wherein the compound is represented bya formula:

wherein ring Ar represents an optionally further substituted aromaticheterocycle or an optionally further substituted C₆₋₁₄ aromatichydrocarbon ring; ring A represents an optionally further substitutedC₆₋₁₄ aromatic hydrocarbon ring or an optionally further substitutedheterocycle; R¹ represents an optionally substituted C₆₋₁₄ aryl group,an optionally substituted C₃₋₁₀ cycloalkyl group or an optionallysubstituted heterocyclic group except that when R¹ is an optionallysubstituted heterocyclic group, R¹ is represented by a formula:

wherein ring B represents an optionally further substituted heterocycle,and

represents a single bond or a double bond, or a formula:

wherein ring D represents an optionally further substitutednitrogen-containing heterocycle, R² represents a hydrogen atom, or R¹and R² are bonded to each other to form an optionally substituted 5- or6-membered aromatic heterocycle or an optionally substituted benzenering.
 2. The method according to claim 1, wherein ring Ar is (I) anaromatic heterocycle optionally substituted by 1 to 3 substituentsselected from (1) a halogen atom, (2) a cyano group, (3) a hydroxygroup, (4) an optionally halogenated C₁₋₆ alkyl group, (5) a C₃₋₁₀cycloalkyl group, (6) an optionally halogenated C₁₋₆ alkoxy group, (7) ahydroxy-C₁₋₆ alkoxy group, (8) a C₃₋₁₀ cycloalkyloxy group, (9) a C₁₋₆alkyl-carbonyl group, (10) a C₁₋₆ alkoxy-carbonyl group, (11) an aminogroup, (12) a mono- or di-C₁₋₆ alkylamino group, (13) a mono- or di-C₁₋₆alkyl-carbonylamino group, (14) a mono- or di-C₃₋₁₀cycloalkyl-carbonylamino group, (15) a 5- to 14-membered aromaticheterocyclic group, and (16) a C₁₋₆ alkylsulfonyl group, or (II) a C₆₋₁₄aromatic hydrocarbon ring optionally substituted by 1 to 3 substituentsselected from (1) a halogen atom, (2) a cyano group, (3) an optionallyhalogenated C₁₋₆ alkyl group, (4) a C₃₋₁₀ cycloalkyl group, (5) anoptionally halogenated C₁₋₆ alkoxy group, (6) a mono- or di-C₁₋₆alkylamino group, (7) a C₁₋₆ alkyl-5- to 14-membered aromaticheterocyclic group, and (8) a C₁₋₆ alkylsulfonyl group; ring A is (I) aC₆₋₁₄ aromatic hydrocarbon ring optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) a cyano group, (3) anoptionally halogenated C₁₋₆ alkyl group, (4) an optionally halogenatedC₁₋₆ alkoxy group, and (5) a C₁₋₆ alkylsulfonyl group, or (II) aheterocycle optionally substituted by 1 to 3 substituents selected from(1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl group, (3)a C₃₋₁₀ cycloalkyl group, (4) an optionally halogenated C₁₋₆ alkoxygroup, (5) a hydroxy-C₁₋₆ alkoxy group, (6) a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup, (7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxygroup, (8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxygroup, (9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group, (10) a mono-or di-C₇₋₁₆ aralkyl phosphate-C₁₋₆ alkoxy group, (11) a 5- to14-membered aromatic heterocyclic group, (12) a 5- to 14-memberedaromatic heterocyclyloxy group, (13) a C₁₋₆ alkylsulfonyl group, and(14) a C₁₋₆ alkylsulfanyl group; R¹ is (I) a C₆₋₁₄ aryl group optionallysubstituted by 1 to 3 substituents selected from (1) a halogen atom, (2)an optionally halogenated C₁₋₆ alkyl group, and (3) a C₁₋₆ alkoxy group,(II) a C₃₋₁₀ cycloalkyl group, or (III) an optionally substitutedheterocyclic group represented by any of (1) a heterocyclic grouprepresented by a formula:

which is selected from pyrazolyl, thienyl and pyridyl and optionallysubstituted by 1 to 3 C₁₋₆ alkyl groups, and (2) a nitrogen-containingheterocyclic group represented by a formula:

which is selected from pyrazol-1-yl, 1,2,3-triazol-1-yl and piperidinyl;R² is a hydrogen atom; or R¹ and R² are bonded to each other to form (I)a 5- or 6-membered aromatic heterocycle optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group, (3) a C₇₋₂₀ alkyl group, (4) ahydroxy-C₁₋₆ alkyl group, (5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group, (6) anoptionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group, (7) a C₃₋₁₀cycloalkyl group, (8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group, (9) a 3- to14-membered non-aromatic heterocyclic group, (10) an optionallyhalogenated C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocyclicgroup, (11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆alkyl group, (12) a carbamoyl-C₁₋₆ alkyl group, (13) an amino-C₁₋₆ alkylgroup, (14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group, (15) afluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group, and (16) a mono-or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group, or (II) a benzene ring optionallysubstituted by one halogen atom.
 3. The method according to claim 2,wherein R¹ represents a C₆₋₁₄ aryl group optionally substituted by 1 to3 substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group and (3) a C₁₋₆ alkoxy group, R² is ahydrogen atom, or R¹ and R² are bonded to each other to form a 5- or6-membered aromatic heterocycle optionally substituted by 1 to 3substituents selected from (1) a halogen atom, (2) an optionallyhalogenated C₁₋₆ alkyl group, (3) a C₇₋₂₀ alkyl group, (4) ahydroxy-C₁₋₆ alkyl group, (5) a C₁₋₆ alkoxy-C₁₋₆ alkyl group, (6) anoptionally halogenated C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl group, (7) a C₃₋₁₀cycloalkyl group, (8) a C₁₋₆ alkoxy-C₇₋₁₆ aralkyl group, (9) a 3- to14-membered non-aromatic heterocyclic group, (10) an optionallyhalogenated C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocyclicgroup, (11) a C₁₋₆ alkyl-3- to 14-membered non-aromatic heterocycle-C₁₋₆alkyl group, (12) a carbamoyl-C₁₋₆ alkyl group, (13) an amino-C₁₋₆ alkylgroup, (14) a C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group, (15) afluorenyl-C₁₋₆ alkoxy-carbonylamino-C₁₋₆ alkyl group, and (16) a mono-or di-C₁₋₆ alkyl nitrogen-containing heterocycle-C₁₋₆alkyl-nitrogen-containing heterocycle-κ²N (boron halide)-C₁₋₆alkyl-carbonylamino-C₁₋₆ alkyl group.
 4. The method according to claim2, wherein ring Ar represents an aromatic heterocycle optionallysubstituted by 1 to 3 substituents selected from (1) a halogen atom, (2)a cyano group, (3) a hydroxy group, (4) an optionally halogenated C₁₋₆alkyl group, (5) a C₃₋₁₀ cycloalkyl group, (6) an optionally halogenatedC₁₋₆ alkoxy group, (7) a hydroxy-C₁₋₆ alkoxy group, (8) a C₃₋₁₀cycloalkyloxy group, (9) a C₁₋₆ alkyl-carbonyl group, (10) a C₁₋₆alkoxy-carbonyl group, (11) an amino group, (12) a mono- or di-C₁₋₆alkylamino group, (13) a mono- or di-C₁₋₆ alkyl-carbonylamino group,(14) a mono- or di-C₃₋₁₀ cycloalkyl-carbonylamino group, (15) a 5- to14-membered aromatic heterocyclic group, and (16) a C₁₋₆ alkylsulfonylgroup.
 5. The method according to claim 4, wherein (I) ring A representsa heterocycle optionally substituted by 1 to 3 substituents selectedfrom (1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl group,(3) a C₃₋₁₀ cycloalkyl group, (4) an optionally halogenated C₁₋₆ alkoxygroup, (5) a hydroxy-C₁₋₆ alkoxy group, (6) a C₁₋₆ alkoxy-C₁₋₆ alkoxygroup, (7) a 3- to 14-membered non-aromatic heterocycle-C₁₋₆ alkoxygroup, (8) a 3- to 14-membered non-aromatic heterocyclyloxy-C₁₋₆ alkoxygroup, (9) a mono- or di-C₁₋₆ alkylamino-C₁₋₆ alkoxy group, (10) a mono-or di-C₇₋₁₆ aralkyl phosphate-C₁₋₆ alkoxy group, (11) a 5- to14-membered aromatic heterocyclic group, (12) a 5- to 14-memberedaromatic heterocyclyloxy group, (13) a C₁₋₆ alkylsulfonyl group, and(14) a C₁₋₆ alkylsulfanyl group, R¹ represents a C₆₋₁₄ aryl groupoptionally substituted by 1 to 3 substituents selected from (1) ahalogen atom, (2) an optionally halogenated C₁₋₆ alkyl group and (3) aC₁₋₆ alkoxy group, and R² represents a hydrogen atom, or (II) ring Arepresents a C₆₋₁₄ aromatic hydrocarbon ring optionally substituted by 1to 3 substituents selected from (1) a halogen atom, (2) a cyano group,(3) an optionally halogenated C₁₋₆ alkyl group, (4) an optionallyhalogenated C₁₋₆ alkoxy group, and (5) a C₁₋₆ alkylsulfonyl group, andR¹ and R² are bonded to each other to form a 5- or 6-membered aromaticheterocycle optionally substituted by 1 to 3 substituents selected from(1) a halogen atom, (2) an optionally halogenated C₁₋₆ alkyl group, (3)a C₇₋₂₀ alkyl group, (4) a hydroxy-C₁₋₆ alkyl group, (5) a C₁₋₆alkoxy-C₁₋₆ alkyl group, (6) an optionally halogenated C₃₋₁₀cycloalkyl-C₁₋₆ alkyl group, (7) a C₃₋₁₀ cycloalkyl group, (8) a C₁₋₆alkoxy-C₇₋₁₆ aralkyl group, (9) a 3- to 14-membered non-aromaticheterocyclic group, (10) an optionally halogenated C₁₋₆ alkyl-3- to14-membered non-aromatic heterocyclic group, (11) a C₁₋₆ alkyl-3- to14-membered non-aromatic heterocycle-C₁₋₆ alkyl group, (12) acarbamoyl-C₁₋₆ alkyl group, (13) an amino-C₁₋₆ alkyl group, (14) a C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, (15) a fluorenyl-C₁₋₆alkoxy-carbonylamino-C₁₋₆ alkyl group, and (16) a mono- or di-C₁₋₆ alkylnitrogen-containing heterocycle-C₁₋₆ alkyl-nitrogen-containingheterocycle-κ2N (boron halide)-C₁₋₆ alkyl-carbonylamino-C₁₋₆ alkylgroup.